Lipophilic active agent infused tobacco leaves and/or tobacco materials and methods of use thereof

ABSTRACT

Aspects described herein relate to lipophilic active agent infused tobacco leaves and/or tobacco materials and methods of use thereof. More particularly, aspects described herein relate to tobacco leaves and/or tobacco materials infused with lipophilic active agents that provide enhanced bioavailability of the lipophilic active agents in a subject, and that mask unpleasant tastes.

PRIORITY

This application is a U.S. National Stage Application under 35 U.S.C. §371, which claims the benefit of International ApplicationPCT/US2019/051135, filed Sep. 13, 2019, which claims the benefit of U.S.Provisional Application No. 62/730,645, filed Sep. 13, 2018; which areincorporated herein by reference in their entirety.

FIELD

Aspects described herein relate to lipophilic active agent infusedtobacco leaves and/or tobacco materials and methods of use thereof. Moreparticularly, aspects described herein relate to tobacco leaves and/ortobacco materials infused with lipophilic active agents that provideenhanced bioavailability of the lipophilic active agents in a subject,and that mask unpleasant tastes.

BACKGROUND

Popular smoking articles, such as cigarettes, have a substantiallycylindrical rod shaped structure and include a charge, roll or column ofsmokable material such as shredded tobacco (e.g., in cut filler form)surrounded by a paper wrapper thereby forming a so-called “tobacco rod.”Normally, a cigarette has a cylindrical filter element aligned in anend-to-end relationship with the tobacco rod. Typically, a filterelement comprises plasticized cellulose acetate tow circumscribed by apaper material known as “plug wrap.” Certain cigarettes incorporate afilter element having multiple segments, and one of those segments cancomprise activated charcoal particles. Typically, the filter element isattached to one end of the tobacco rod using a circumscribing wrappingmaterial known as “tipping paper.” It also has become desirable toperforate the tipping material and plug wrap, in order to providedilution of drawn mainstream smoke with ambient air. A cigarette isemployed by a smoker by lighting one end thereof and burning the tobaccorod. The smoker then receives mainstream smoke into his/her mouth bydrawing on the opposite end (e.g., the filter end) of the cigarette.

The tobacco used for cigarette manufacture is typically used in blendedform. For example, certain popular tobacco blends, commonly referred toas “American blends,” comprise mixtures of flue-cured tobacco, burleytobacco and Oriental tobacco, and in many cases, certain processedtobaccos, such as reconstituted tobacco and processed tobacco stems. Theprecise amount of each type of tobacco within a tobacco blend used forthe manufacture of a particular cigarette brand varies from brand tobrand. However, for many tobacco blends, flue-cured tobacco makes up arelatively large proportion of the blend, while Oriental tobacco makesup a relatively small proportion of the blend. See, for example, TobaccoEncyclopedia, Voges (Ed.) p. 44-45 (1984), Browne, The Design ofCigarettes, 3^(rd) Ed., p. 43 (1990) and Tobacco Production, Chemistryand Technology, Davis et al. (Eds.) p. 346 (1999).

Tobacco also may be enjoyed in a so-called “smokeless” form.Particularly popular smokeless tobacco products are employed byinserting some form of processed tobacco or tobacco-containingformulation into the mouth of the user. Various types of smokelesstobacco products are set forth in U.S. Pat. No. 1,376,586 to Schwartz;U.S. Pat. No. 3,696,917 to Levi; U.S. Pat. No. 4,513,756 to Pittman etal.; U.S. Pat. No. 4,528,993 to Sensabaugh, Jr. et al.; U.S. Pat. No.4,624,269 to Story et al.; U.S. Pat. No. 4,987,907 to Townsend; U.S.Pat. No. 5,092,352 to Sprinkle, III et al.; and U.S. Pat. No. 5,387,416to White et al.; U.S. Pat. Appl. Pub. No. 2005/0244521 to Strickland etal.; PCT WO 04/095959 to Arnarp et al.; PCT WO 05/063060 to Atchley etal.; PCT WO 05/004480 to Engstrom; PCT WO 05/016036 to Bjorkholm; andPCT WO 05/041699 to Quinter et al., each of which is incorporated hereinby reference. See, for example, the types of smokeless tobaccoformulations, ingredients, and processing methodologies set forth inU.S. Pat. No. 6,953,040 to Atchley et al. and U.S. Pat. No. 7,032,601 toAtchley et al., each of which is incorporated herein by reference.

One type of smokeless tobacco product is referred to as “snuff.”Representative types of moist snuff products, commonly referred to as“snus,” are manufactured in Europe, particularly in Sweden, by orthrough companies such as Swedish Match AB, Fiedler & Lundgren AB,Gustavus AB, Skandinavisk Tobakskompagni A/S, and Rocker Production AB.Snus products available in the U.S.A. are marketed under the tradenamesCamel Snus Frost, Camel Snus Original and Camel Snus Spice by R. J.Reynolds Tobacco Company. Representative smokeless tobacco products alsoare marketed under the tradenames Oliver Twist by House of Oliver TwistA/S; Copenhagen, Skoal, SkoalDry, Rooster, Red Seal, Husky, and Revel byU.S. Smokeless Tobacco Co.; “taboka” by Philip Morris USA; and LeviGarrett, Peachy, Taylor's Pride, Kodiak, Hawken Wintergreen, Grizzly,Dental, Kentucky King, and Mammoth Cave by Conwood Sales Co., L.P. Seealso, for example, Bryzgalov et al., 1N1800 Life Cycle Assessment,Comparative Life Cycle Assessment of General Loose and Portion Snus(2005). In addition, certain quality standards associated with snusmanufacture have been assembled as a so-called GothiaTek standard.

Through the years, various treatment methods and additives have beenproposed for altering the overall character or nature of tobaccomaterials utilized in tobacco compositions. For example, additives ortreatment processes are sometimes utilized in order to alter thechemistry or sensory properties of the tobacco material, or in the caseof smokable tobacco materials, to alter the chemistry or sensoryproperties of mainstream smoke generated by smoking articles includingthe tobacco material. In some cases, a heat treatment process can beused to impart a desired color or visual character to the tobaccomaterial, desired sensory properties to the tobacco material, or adesired physical nature or texture to the tobacco material.

In particular, the sensory attributes of cigarette smoke can be enhancedby incorporating flavoring materials into various components of acigarette. See, Leffingwell et al., Tobacco Flavoring for SmokingProducts, R.J. Reynolds Tobacco Company (1972). Exemplary flavoringadditives include menthol and products of Maillard reactions, such aspyrazines, aminosugars, and Amadori compounds. Various processes forpreparing flavorful and aromatic compositions for use in tobaccocompositions are set forth in U.S. Pat. No. 3,424,171 to Rooker; U.S.Pat. No. 3,476,118 to Luttich; U.S. Pat. No. 4,150,677 to Osborne, Jr.et al.; U.S. Pat. No. 4,986,286 to Roberts et al.; U.S. Pat. No.5,074,319 to White et al.; U.S. Pat. No. 5,099,862 to White et al.; U.S.Pat. No. 5,235,992 to Sensabaugh, Jr.; U.S. Pat. No. 6,298,858 toColeman, III et al.; U.S. Pat. No. 6,325,860 to Coleman, III et al.;U.S. Pat. No. 6,428,624 to Coleman, III et al.; U.S. Pat. No. 6,440,223to Dube et al.; U.S. Pat. No. 6,499,489 to Coleman, III; and U.S. Pat.No. 6,591,841 to White et al.; U.S. Pat. Appl. Publication No.2004/0173228 to Coleman, III; and U.S. application Ser. No. 12/191,751to Coleman, III et al., filed Aug. 14, 2008, each of which isincorporated herein by reference. Such processes often include theapplication of heat to a tobacco material, which can result in reactionsthat form certain byproducts.

The sensory attributes of smokeless tobacco can also be enhanced byincorporation of certain flavoring materials. See, for example, U.S.Pat. Appl. Pub. Nos. 2002/0162562 to Williams; 2002/0162563 to Willams;2003/0070687 to Atchley et al.; 2004/0020503 to Williams, 2005/0178398to Breslin et al.; 2006/0191548 to Strickland et al.; 2007/0062549 toHolton, Jr. et al.; 2007/0186941 to Holton, Jr. et al.; 2007/0186942 toStrickland et al.; 2008/0029110 to Dube et al.; 2008/0029116 to Robinsonet al.; 2008/0029117 to Mua et al.; 2008/0173317 to Robinson et al.; and2008/0209586 to Neilsen et al., each of which is incorporated herein byreference.

Accordingly, it would be desirable in the art to provide further methodsfor altering the character and nature of tobacco (and tobaccocompositions and formulations) useful in smoking articles or smokelesstobacco products, including enhancement of bioavailability of activeagents, masking of unpleasant tastes, and the incorporation ofadditional active agents.

SUMMARY

To address the foregoing problems, in whole or in part, and/or otherproblems that may have been observed by persons skilled in the art, thepresent disclosure provides compositions and methods as described by wayof example as set forth below.

In one aspect, lipophilic active agent infused tobacco leaves and/ortobacco materials are provided, comprising:

(a) a therapeutically effective amount of a lipophilic active agent,wherein the lipophilic active agent is selected from the groupconsisting of cannabinoids, terpenes and terpenoids, NSAIDs, vitamins,nicotine compounds, phosphodiesterase type 5 (PDE5) inhibitors, Macaextract, estrogen, progestin, testosterone, buprenorphine, andscopolamine;

(b) a bioavailability enhancing agent, wherein the bioavailabilityenhancing agent enhances the bioavailability of the lipophilic activeagent in a subject; and

(c) tobacco leaves and/or tobacco materials.

In other aspects, the lipophilic active agent infused tobacco leavesand/or tobacco materials are obtainable by the steps of:

(i) contacting the tobacco leaves and/or tobacco materials with an oilcomprising the lipophilic active agent and the bioavailability enhancingagent; and

(ii) dehydrating the tobacco leaves and/or tobacco materials;

thereby producing the lipophilic active agent infused tobacco leavesand/or tobacco materials. In further aspects, step (i) comprisessaturating the tobacco leaves and/or tobacco materials in the oilcomprising the lipophilic active agent and the bioavailability enhancingagent. In further aspects, the bioavailability enhancing agent is anedible oil comprising long chain fatty acids, medium chain fatty acids,and/or a combination of both medium and long chain fatty acids.

Tobacco compositions comprising any of the lipophilic active agentinfused tobacco leaves and/or tobacco materials described herein arealso provided.

Smokeless tobacco compositions comprising any of the lipophilic activeagent infused tobacco leaves and/or tobacco materials described hereinare also provided.

In another aspect, a process is provided for making lipophilic activeagent infused tobacco leaves and/or tobacco materials comprising thesteps of:

(a) contacting tobacco leaves and/or tobacco materials with an oilcomprising a lipophilic active agent and a bioavailability enhancingagent; and

(b) dehydrating the tobacco leaves and/or tobacco materials;

thereby producing lipophilic active agent infused tobacco leaves and/ortobacco materials; wherein the lipophilic active agent infused tobaccoleaves and/or tobacco materials comprise a therapeutically effectiveamount of the lipophilic active agent, and further wherein:

(i) the lipophilic active agent is selected from the group consisting ofcannabinoids, terpenes and terpenoids, NSAIDs, vitamins, nicotinecompounds, phosphodiesterase type 5 (PDE5) inhibitors, Maca extract,estrogen, progestin, testosterone, buprenorphine, and scopolamine and

(ii) the bioavailability enhancing agent enhances the bioavailability ofthe lipophilic active agent.

In other aspects, step (a) comprises saturating the food product in theoil comprising the lipophilic active agent and the bioavailabilityenhancing agent. In further aspects, the bioavailability enhancing agentis an edible oil comprising long chain fatty acids, medium chain fattyacids, and/or a combination of both medium and long chain fatty acids.In further aspects, step (a) further comprises contacting the tobaccoleaves and/or tobacco materials with a flavoring agent, particularlywherein the flavoring agent is selected from the group consisting ofvanilla, vanillin, ethyl vanillin, orange oil, peppermint oil,strawberry, raspberry, and mixtures thereof.

Tobacco compositions comprising any of the lipophilic active agentinfused tobacco leaves and/or tobacco materials made by any of theprocesses described herein are also provided.

Smokeless tobacco compositions comprising any of the lipophilic activeagent infused tobacco leaves and/or tobacco materials made by any of theprocesses described herein are also provided.

Other compositions, methods, features, and advantages of the inventionwill be or will become apparent to one with skill in the art uponexamination of the following detailed description. It is intended thatall such additional compositions, methods, features, and advantages beincluded within this description, be within the scope of the invention,and be protected by the accompanying claims.

DETAILED DESCRIPTION

The present invention is directed to lipophilic active agent infusedtobacco leaves and/or tobacco materials and methods for makinglipophilic active agent infused tobacco leaves and/or tobacco materials.More particularly, aspects described herein relate to lipophilic activeagent infused tobacco leaves and/or tobacco materials that provideenhanced bioavailability of the lipophilic active agents in a subject,and/or that mask unpleasant tastes of lipophilic active agents and/ortobacco.

The lipophilic active agent infused tobacco leaves and/or tobaccomaterials of the invention can be used as an additive for a smokingarticle (e.g., as part of the smokable blend or as an additive to thefilter or wrapping paper of the smoking article) or as a smokelesstobacco composition, such as loose moist snuff, loose dry snuff, chewingtobacco, pelletized tobacco pieces, extruded or formed tobacco strips,pieces, rods, or sticks, finely divided ground powders, finely dividedor milled agglomerates of powdered pieces and components, flake-likepieces, molded processed tobacco pieces, pieces of tobacco-containinggum, rolls of tape-like films, readily water dissolvable orwater-dispersible formats such as films, strips, or powders,shelf-stable ready to drink beverage compositions, and pharmaceuticalcompositions formulated in unit dosage form, including but not limitedto tablets, caplets, capsules, lozenges, films, strips, gelcaps, andsyrups. Such pharmaceutical compositions may also comprise one or morepharmaceutically acceptable excipient(s), which are pharmacologicallyinactive components such as a diluent, disintegrant, carrier, or thelike. Additional information concerning pharmaceutical formulations isfound in Remington (2006) The Science and Practice of Pharmacy, 21^(st)edition, Lippincott Williams & Wilkins.

The lipophilic active agent infusion process of the invention can alsobe incorporated into conventional tobacco treatment processes, such asprocesses adapted to faun flavorful and aromatic compounds (e.g.,Maillard reaction products), processes adapted for pasteurization oftobacco compositions, processes for preparing tobacco casing products,reconstituted tobacco

processes (e.g., cast sheet and paper-making

reconstituted tobacco processes), tobacco extraction processes,reordering processes, toasting processes, steam treatments, and dryingprocesses.

Accordingly, the lipophilic active agent infused tobacco leaves and/ortobacco materials of the invention can be used within exemplarytechnologies for conventional and smokeless tobacco compositions andprocesses described in the published U.S. patent applications listedAppendix D, each of which are incorporated herein in their entireties.

Compositions Lipophilic Active Agent Infused Tobacco Leaves and/orTobacco Materials

In one aspect, lipophilic active agent infused tobacco leaves and/ortobacco materials are provided, comprising:

-   -   (a) a therapeutically effective amount of a lipophilic active        agent, wherein the lipophilic active agent is selected from the        group consisting of cannabinoids, terpenes and terpenoids,        NSAIDs, vitamins, nicotine compounds, phosphodiesterase type 5        (PDE5) inhibitors, Maca extract, estrogen, progestin,        testosterone, buprenorphine, and scopolamine    -   (b) a bioavailability enhancing agent, wherein the        bioavailability enhancing agent enhances the bioavailability of        the lipophilic active agent in a subject; and    -   (c) tobacco leaves and/or tobacco materials.

In another aspect, the bioavailability enhancing agent comprises anedible oil comprising long chain fatty acids. In another aspect, thebioavailability enhancing agent comprises an edible oil comprising amedium chain fatty acid. In further aspects, the bioavailabilityenhancing agent is a combination of edible oils that include both mediumand long chain fatty acids.

In another aspect, the lipophilic active agent infused tobacco leavesand/or tobacco materials are obtainable by the steps of:

-   -   (i) contacting the tobacco leaves and/or tobacco materials with        an oil comprising the lipophilic active agent and the        bioavailability enhancing agent; and    -   (ii) dehydrating the tobacco leaves and/or tobacco materials;        thereby producing the lipophilic active agent infused tobacco        leaves and/or tobacco materials.

In a further aspect, step (i) comprises saturating the tobacco leavesand/or tobacco materials in the oil comprising the lipophilic activeagent and the bioavailability enhancing agent. In yet another aspect,the lipophilic active agent infused tobacco leaves and/or tobaccomaterials further comprise a flavoring agent. In a further aspect, thelipophilic active agent infused food tobacco leaves and/or tobaccomaterials are lyophilized.

Tobacco leaves and/or tobacco materials as used in the compositions andmethods of the present invention may vary. The tobacco leaves and/ortobacco materials may include types of tobaccos such as flue-curedtobacco, burley tobacco, sun-cured tobacco (e.g., Oriental tobacco orIndian Kurnool), Maryland tobacco, dark tobacco, dark-fired tobacco,dark air cured (e.g., passanda, cubano, jatin and bezuki tobaccos) orlight air cured (e.g., North Wisconsin and galpoa tobaccos), and Rusticatobaccos, as well as other rare or specialty tobaccos or even green oruncured tobaccos.

Descriptions of various types of tobaccos, growing practices, harvestingpractices and curing practices are set forth in Tobacco Production,Chemistry and Technology, Davis et al. (Eds.) (1999), which isincorporated herein by reference. See, also, the types of tobaccos thatare set forth in U.S. Pat. No. 4,660,577 to Sensabaugh, Jr. et al.; U.S.Pat. No. 5,387,416 to White et al.; and U.S. Pat. No. 6,730,832 toDominguez et al., each of which is incorporated herein by reference.

Most preferably, the tobacco materials are those that have beenappropriately cured and aged. Especially preferred techniques andconditions for curing flue-cured tobacco are set forth in Nestor et al.,Beitrage Tabakforsch. Int., 20 (2003) 467-475 and U.S. Pat. No.6,895,974 to Peele, which are incorporated herein by reference.Representative techniques and conditions for air curing tobacco are setforth in Roton et al., Beitrage Tabakforsch. Int., 21 (2005) 305-320 andStaaf et al., Beitrage Tabakforsch. Int., 21 (2005) 321-330, which areincorporated herein by reference.

Certain types of unusual or rare tobaccos can be sun cured. Manners andmethods for improving the smoking quality of Oriental tobaccos are setforth in U.S. Pat. No. 7,025,066 to Lawson et al., which is incorporatedherein by reference. Representative Oriental tobaccos include katerini,prelip, komotini, xanthi and yambol tobaccos. Tobacco compositionsincluding dark air cured tobacco are set forth in US Patent Appl. Pub.No. 2008/0245377 to Marshall et al., which is incorporated herein byreference.

Lipophilic active agent infused tobacco leaves and/or tobacco materialsof the present invention, such as lipophilic active agent infusedtobacco leaves and/or tobacco materials intended to be used in asmokeless form, may incorporate a single type of tobacco (e.g., in aso-called “straight grade” form). For example, the tobacco within thecompositions and methods of the present invention may be composed solelyof flue-cured tobacco (e.g., all of the tobacco may be composed, orderived from, either flue-cured tobacco lamina or a mixture offlue-cured tobacco lamina and flue-cured tobacco stem). The tobaccowithin the compositions and methods of the present invention also mayhave a so-called “blended” form. For example, the tobacco within thecompositions and methods of the present invention may include a mixtureof parts or pieces of flue-cured, burley (e.g., Malawi burley tobacco)and Oriental tobaccos (e.g., as tobacco composed of, or derived from,tobacco lamina, or a mixture of tobacco lamina and tobacco stem). Forexample, a representative blend may incorporate about 30 to about 70parts burley tobacco (e.g., lamina, or lamina and stem), and about 30 toabout 70 parts flue cured tobacco (e.g., stem, lamina, or lamina andstem) on a dry weight basis. Other exemplary tobacco blends incorporateabout 75 parts flue-cured tobacco, about 15 parts burley tobacco, andabout 10 parts Oriental tobacco; or about 65 parts flue-cured tobacco,about 25 parts burley tobacco, and about 10 parts Oriental tobacco; orabout 65 parts flue-cured tobacco, about 10 parts burley tobacco, andabout 25 parts Oriental tobacco; on a dry weight basis. Other exemplarytobacco blends incorporate about 20 to about 30 parts Oriental tobaccoand about 70 to about 80 parts flue-cured tobacco.

As used herein, “tobacco leaves and/or tobacco materials” includes wholeor partial leaves of tobacco, processed tobacco parts or pieces, curedand aged tobacco in essentially natural lamina or stem form, a tobaccoextract, extracted tobacco pulp (e.g., using water as a solvent), or amixture of the foregoing (e.g., a mixture that combines extractedtobacco pulp with granulated cured and aged natural tobacco lamina). Thetobacco leaves and/or tobacco materials most preferably includes tobaccolamina, or tobacco lamina and stem mixture. Tobacco mixturesincorporating a predominant amount of tobacco lamina, relative totobacco stem, are preferred. Most preferably, the tobacco lamina andstem are used in an unextracted form, that is, such that the extractableportion (e.g., the water soluble portion) is present within theunextractable portion (e.g., the tobacco pulp) in a manner comparable tothat of natural tobacco provided in a cured and aged form. Portions ofthe tobacco may have processed forms, such as processed tobacco stems(e.g., cut-rolled stems, cut-rolled-expanded stems or cut-puffed stems),or volume expanded tobacco (e.g., puffed tobacco, such as dry iceexpanded tobacco (DIET)). See, for example, the tobacco expansionprocesses set forth in U.S. Pat. No. 4,340,073 to de la Burde et al.;U.S. Pat. No. 5,259,403 to Guy et al.; and U.S. Pat. No. 5,908,032 toPoindexter, et al.; and U.S. Patent Appl. Pub. No. 2004/0182404 toPoindexter, et al., all of which are incorporated by reference. Inaddition, the tobacco leaves and/or tobacco materials optionally mayincorporate tobacco that has been fermented. See, also, the types oftobacco processing techniques set forth in PCT WO 05/063060 to Atchleyet al., which is incorporated herein by reference.

The tobacco leaves and/or tobacco materials within the compositions andmethods of the present invention are typically provided in a shredded,ground, granulated, fine particulate, or powder form. Most preferably,the tobacco leaves and/or tobacco materials is employed in the form ofparts or pieces that have an average particle size less than that of theparts or pieces of shredded tobacco used in so-called “fine cut” tobaccoproducts. Typically, the very finely divided tobacco particles or piecesare sized to pass through a screen of about 18 Tyler mesh, generally aresized to pass a screen of about 20 Tyler mesh, often are sized to passthrough a screen of about 50 Tyler mesh, frequently are sized to passthrough a screen of about 60 Tyler mesh, may even be sized to passthrough a screen of 100 Tyler mesh, and further may be sized so as topass through a screen of 200 Tyler mesh. If desired, air classificationequipment may be used to ensure that small sized tobacco particles ofthe desired sizes, or range of sizes, may be collected. In oneembodiment, the tobacco material is in particulate form sized to passthrough an 18 Tyler mesh, but not through a 60 Tyler mesh. If desired,differently sized pieces of granulated tobacco may be mixed together.Typically, the very finely divided tobacco particles or pieces suitablefor snus products have a particle size greater than −8 Tyler mesh, often−8 to +100 Tyler mesh, frequently −18 to +60 Tyler mesh.

The manner by which the tobacco is provided in a finely divided orpowder type of form may vary. Preferably, tobacco parts or pieces arecomminuted, ground or pulverized into a powder type of form usingequipment and techniques for grinding, milling, or the like. Mostpreferably, the tobacco is relatively dry in form during grinding ormilling, using equipment such as hammer mills, cutter heads, air controlmills, or the like. For example, tobacco parts or pieces may be groundor milled when the moisture content thereof is less than about 15 weightpercent to less than about 5 weight percent.

Tobacco extracts are useful as components of the tobacco leaves and/ortobacco materials within the compositions and methods of the presentinvention. Extracts can be used in solid form (e.g., spray-dried orfreeze-dried form), in liquid form, in semi-solid form, or the like.Exemplary tobacco extracts and extraction techniques are set forth, forexample, in U.S. Pat. No. 4,150,677 to Osborne, Jr. et al.; U.S. Pat.No. 4,967,771 to Fagg et al.; U.S. Pat. No. 5,005,593 to Fagg et al.;U.S. Pat. No. 5,148,819 to Fagg; and U.S. Pat. No. 5,435,325 to Clapp etal., all of which are incorporated by reference herein. Various tobaccoextraction and reconstitution methodologies are set forth in U.S. Pat.No. 5,065,775 to Fagg; U.S. Pat. No. 5,360,022 to Newton; and U.S. Pat.No. 5,131,414 to Fagg, all of which are incorporated by referenceherein. See also, the tobacco extract treatment methodologies set forthin U.S. Pat. No. 5,131,415 to Munoz et al. and U.S. Pat. No. 5,318,050to Gonzalez-Parra, both of which are incorporated by reference herein.

Suitable known reconstituted tobacco processing techniques, such aspaper-making techniques or casting-type processes, can be employed inconjunction with the processes of the invention. See, for example, thetypes of paper-making processes set forth in U.S. Pat. No. 3,398,754 toTughan; U.S. Pat. No. 3,847,164 to Mattina; U.S. Pat. No. 4,131,117 toKite; U.S. Pat. No. 4,270,552 to Jenkins; U.S. Pat. No. 4,308,877 toMattina; U.S. Pat. No. 4,341,228 to Keritsis; U.S. Pat. No. 4,421,126 toGellatly; U.S. Pat. No. 4,706,692 to Gellatly; U.S. Pat. No. 4,962,774to Thomasson; U.S. Pat. No. 4,941,484 to Clapp; U.S. Pat. No. 4,987,906to Young; U.S. Pat. No. 5,056,537 to Brown; U.S. Pat. No. 5,143,097 toSohn; U.S. Pat. No. 5,159,942 to Brinkley et al.; U.S. Pat. No.5,325,877 to Young; U.S. Pat. No. 5,445,169 to Brinkley; U.S. Pat. No.5,501,237 to Young; U.S. Pat. No. 5,533,530 to Young; which areincorporated herein by reference. See, for example, the castingprocesses set forth in U.S. Pat. No. 3,353,541 to Hind; U.S. Pat. No.3,399,454 to Hind; U.S. Pat. No. 3,483,874 to Hind; U.S. Pat. No.3,760,815 to Deszyck; U.S. Pat. No. 4,674,519 to Keritsis; U.S. Pat. No.4,972,854 to Kiernan; U.S. Pat. No. 5,023,354 to Hickle; U.S. Pat. No.5,099,864 to Young; U.S. Pat. No. 5,101,839 to Jakob; U.S. Pat. No.5,203,354 to Hickle; U.S. Pat. No. 5,327,917 to Lekwauwa; U.S. Pat. No.5,339,838 to Young; U.S. Pat. No. 5,598,868 to Jakob; U.S. Pat. No.5,715,844 to Young; U.S. Pat. No. 5,724,998 to Gellatly; and U.S. Pat.No. 6,216,706 to Kumar; and EPO 565360; EPO 1055375 and PCT WO 98/01233;which are incorporated herein by reference. Extracts, extractedmaterials, and slurries used in traditional types of reconstitutedtobacco processes can be employed as ingredients in tobacco formulationsof the invention.

The processes of the invention can be used in connection with anytobacco treatment process where the application of heat is involved, andin conjunction with heat treatment processing aids or additives or inconjunction with ingredients such as casing components. See, forexample, the casing materials and methods set forth in U.S. Pat. No.4,177,822 to Bryant, Jr. et al.; U.S. Pat. No. 4,306,577 to Wu et al.;U.S. Pat. No. 4,449,541 to Mays et al.; U.S. Pat. No. 4,537,204 toGaisch et al.; U.S. Pat. No. 4,819,668 to Shelar et al.; and U.S. Pat.No. 4,836,224 to Lawson et al., each of which is incorporated byreference herein.

Tobacco Compositions Comprising Lipophilic Active Agent Infused TobaccoLeaves and/or Tobacco Materials

The lipophilic active agent infused tobacco leaves and/or tobaccomaterials of the present invention are useful as additives for themanufacture of smoking articles (also referenced herein as “tobaccocompositions”). For example, lipophilic active agent infused tobaccoleaves and/or tobacco materials prepared in accordance with the presentinvention can be mixed with casing materials and applied to tobacco as acasing ingredient, incorporated into smoking articles as a top dressingingredient, or incorporated into reconstituted tobacco materials. Stillfurther, the lipophilic active agent infused tobacco leaves and/ortobacco materials of the invention can be incorporated into a cigarettefilter (e.g., in the filter plug, plug wrap, or tipping paper) orincorporated into cigarette wrapping paper, preferably on the insidesurface, during the cigarette manufacturing process. The lipophilicactive agent infused tobacco leaves and/or tobacco materials can also beused as an additive within certain aerosol-generating electronic smokingarticles, such as those described in U.S. Pat. Appl. Pub. No.2008/0092912 to Robinson et al., which is incorporated by referenceherein in its entirety.

The lipophilic active agent infused tobacco leaves and/or tobaccomaterials of the invention may also be incorporated into the tobaccoblends, representative cigarette components, and representativecigarettes manufactured therefrom, set forth in U.S. Pat. No. 4,836,224to Lawson et al.; U.S. Pat. No. 4,924,888 to Perfetti et al.; U.S. Pat.No. 5,056,537 to Brown et al.; U.S. Pat. No. 5,220,930 to Gentry; andU.S. Pat. No. 5,360,023 to Blakley et al.; US Pat. Application2002/0000235 to Shafer et al.; and PCT WO 02/37990. Those tobaccomaterials also can be employed for the manufacture of those types ofcigarettes that are described in U.S. Pat. No. 4,793,365 to Sensabaugh;U.S. Pat. No. 4,917,128 to Clearman et al.; U.S. Pat. No. 4,947,974 toBrooks et al.; U.S. Pat. No. 4,961,438 to Korte; U.S. Pat. No. 4,920,990to Lawrence et al.; U.S. Pat. No. 5,033,483 to Clearman et al.; U.S.Pat. No. 5,074,321 to Gentry et al.; U.S. Pat. No. 5,105,835 to Drewettet al.; U.S. Pat. No. 5,178,167 to Riggs et al.; U.S. Pat. No. 5,183,062to Clearman et al.; U.S. Pat. No. 5,211,684 to Shannon et al.; U.S. Pat.No. 5,247,949 to Deevi et al.; U.S. Pat. No. 5,551,451 to Riggs et al.;U.S. Pat. No. 5,285,798 to Banerjee et al.; U.S. Pat. No. 5,593,792 toFarrier et al.; U.S. Pat. No. 5,595,577 to Bensalem et al.; U.S. Pat.No. 5,816,263 to Counts et al.; U.S. Pat. No. 5,819,751 to Barnes etal.; U.S. Pat. No. 6,095,153 to Beven et al.; U.S. Pat. No. 6,311,694 toNichols et al.; and U.S. Pat. No. 6,367,481 to Nichols, et al.; and PCTWO 97/48294 and PCT WO 98/16125. See, also, those types of commerciallymarketed cigarettes described Chemical and Biological Studies on NewCigarette Prototypes that Heat Instead of Burn Tobacco, R. J. ReynoldsTobacco Company Monograph (1988) and Inhalation Toxicology, 12:5, p.1-58 (2000).

The lipophilic active agent infused tobacco leaves and/or tobaccomaterials of the invention can also be used as a smokeless tobaccoproduct or incorporated as an additive in a smokeless tobacco product.Various types of smokeless tobacco products are set forth in U.S. Pat.No. 1,376,586 to Schwartz; U.S. Pat. No. 3,696,917 to Levi; U.S. Pat.No. 4,513,756 to Pittman et al.; U.S. Pat. No. 4,528,993 to Sensabaugh,Jr. et al.; U.S. Pat. No. 4,624,269 to Story et al.; U.S. Pat. No.4,987,907 to Townsend; U.S. Pat. No. 5,092,352 to Sprinkle, III et al.;and U.S. Pat. No. 5,387,416 to White et al.; US Pat. App. Pub. No.2005/0244521 to Strickland et al.; PCT WO 04/095959 to Arnarp et al.;PCT WO 05/063060 to Atchley et al.; PCT WO 05/004480 to Engstrom; PCT WO05/016036 to Bjorkholm; and PCT WO 05/041699 to Quinter et al., each ofwhich is incorporated herein by reference. See also, the types ofsmokeless tobacco formulations, ingredients, and processingmethodologies set forth in U.S. Pat. No. 6,953,040 to Atchley et al. andU.S. Pat. No. 7,032,601 to Atchley et al.; U.S. Pat. Appl. Pub. Nos.2002/0162562 to Williams; 2002/0162563 to Willams; 2003/0070687 toAtchley et al.; 2004/0020503 to Williams, 2005/0178398 to Breslin etal.; 2006/0191548 to Strickland et al.; 2007/0062549 to Holton, Jr. etal.; 2007/0186941 to Holton, Jr. et al.; 2007/0186942 to Strickland etal.; 2008/0029110 to Dube et al.; 2008/0029116 to Robinson et al.;2008/0029117 to Mua et al.; 2008/0173317 to Robinson et al.; and2008/0209586 to Neilsen et al., each of which is incorporated herein byreference.

The relative amount of lipophilic active agent infused tobacco leavesand/or tobacco materials within tobacco formulations may vary.Preferably, the amount of lipophilic active agent infused tobacco leavesand/or tobacco materials within the tobacco formulation is at leastabout 10 percent or at least about 25 percent, on a dry weight basis ofthe formulation. In certain instances, the amounts of other componentswithin the tobacco formulation may exceed about 40 percent, on a dryweight basis. A typical range of tobacco material within the formulationis about 10 to about 60 weight percent, more often about 20 to about 40weight percent on a dry basis.

Tobacco products differ uniquely from food products with regard tocertain reactions, such as a reaction between asparagine and reducingsugars. With smoking tobacco products (e.g., cigarettes, cigars, pipetobacco), the temperature gradient during use is much higher than thetemperature encountered in foods during cooking, which can lead to anincreased rate of reaction. With certain smokeless tobacco products, thepH can be much higher than the pH of foods and, during processing,heating the tobacco with an increased pH may enhance the rate of certainreactions. Therefore, inhibition of certain reactions can beparticularly challenging when dealing with tobacco products.

Accordingly, exemplary additives to tobacco formulations that includelipophilic active agent infused tobacco leaves and/or tobacco materialsof the present invention include amino acids, compositions incorporatingdi- and trivalent cations, asparaginase, certain non-reducingsaccharides, certain reducing agents, phenolic compounds (e.g.,compounds having at least one phenolic functionality), certain compoundshaving at least one free thiol group or functionality, oxidizing agents,oxidation catalysts, rosemary extract (or other plant extracts derivedfrom herbal or botanical sources), and combinations thereof. Withoutbeing bound of a theory of operation, it is believed that theseadditives are capable of inhibiting reaction of asparagine to formacrylamide, either by providing competing reactions that preferentiallyreact with available reducing sugars, by chemical interaction withasparagine that renders it unable to react with reducing sugars, bychemical interaction with reaction intermediates, or by chemicalinteraction with acrylamide. Use of certain additives according to theinvention is described in U.S. Pat. No. 7,037,540 to Elder et al. andU.S. Pat. No. 7,267,834 to Elder et al.; and U.S. Pat. Appl. Pub. Nos.2004/0058046 to Zyzak et al; 2005/0196504 to Finley; 2006/0194743 to Okuet al; 2007/0141225 to Elder et al.; 2007/0141227 to Boudreaux et al.;and 2007/0166439 to Soe et al., which are incorporated by reference intheir entirety.

The amount of the additive present in tobacco formulations that includelipophilic active agent infused tobacco leaves and/or tobacco materialsof the present invention will vary depending on the desired character ofthe tobacco formulation and the type of additive selected. Typically,the amount of additive is at least about 0.01 dry weight percent, moreoften at least about 0.1 dry weight percent, and most often at leastabout 1 dry weight percent. The additive is present in an amounttypically less than about 15 dry weight percent, such as less than about10 weight percent or less than about 8 weight percent. In oneembodiment, the amount of the additive is about 1 dry weight percent toabout 5 dry weight percent.

In some embodiments, the tobacco formulations that include lipophilicactive agent infused tobacco leaves and/or tobacco materials of thepresent invention are smokeless tobacco compositions. Such smokelesstobacco compositions, in addition to tobacco, water, and additives asnoted elsewhere herein, also typically include additional componentssuch as flavorants, fillers, binders, pH adjusters, buffering agents,colorants, disintegration aids, antioxidants, humectants, andpreservatives.

Exemplary flavorants that can be used are components, or suitablecombinations of those components, that act to alter the bitterness,sweetness, sourness, or saltiness of the smokeless tobacco product,enhance the perceived dryness or moistness of the formulation, or thedegree of tobacco taste exhibited by the formulation. Types offlavorants include salts (e.g., sodium chloride, potassium chloride,sodium citrate, potassium citrate, sodium acetate, potassium acetate,and the like), natural sweeteners (e.g., fructose, sucrose, glucose,maltose, mannose, galactose, lactose, and the like), artificialsweeteners (e.g., sucralose, saccharin, aspartame, acesulfame K,neotame, and the like); and mixtures thereof. The amount of flavorantsutilized in the tobacco composition can vary, but is typically up toabout 10 dry weight percent, and certain embodiments are characterizedby a flavorant content of at least about 1 dry weight percent, such asabout 1 to about 10 dry weight percent. Combinations of flavorants areoften used, such as about 0.1 to about 2 dry weight percent of anartificial sweetener and about 0.5 to about 8 dry weight percent of asalt such as sodium chloride.

Exemplary filler materials include vegetable fiber materials such assugar beet fiber materials (e.g., FIBREX® brand filler available fromInternational Fiber Corporation), oats or other cereal grain (includingprocessed or puffed grains), bran fibers, starch, or other modified ornatural cellulosic materials such as microcrystalline cellulose.Additional specific examples include corn starch, maltodextrin,dextrose, calcium carbonate, calcium phosphate, lactose, manitol,xylitol, and sorbitol. The amount of filler utilized in the tobaccocomposition can vary, but is typically up to about 50 dry weightpercent, and certain embodiments are characterized by a filler contentof at least about 10 dry weight percent, such as about 20 to about 50dry weight percent. Combinations of fillers are often used, such asabout 2 to about 8 dry weight percent of calcium carbonate, about 10 toabout 20 dry weight percent of rice flour, and about 10 to about 20weight percent of maltodextrin.

Typical binders include povidone, sodium carboxymethylcellulose andother modified cellulosic materials, sodium alginate, xanthan gum,starch-based binders, gum arabic, pectin, carrageenan, pullulan, zein,and the like. The amount of binder utilized in the tobacco compositioncan vary, but is typically up to about 30 dry weight percent, andcertain embodiments are characterized by a binder content of at leastabout 5 dry weight percent, such as about 5 to about 30 dry weightpercent.

Preferred pH adjusters or buffering agents provide and/or buffer withina pH range of about 6 to about 10, and exemplary agents include metalhydroxides, metal carbonates, metal bicarbonates, and mixtures thereofSpecific exemplary materials include sodium hydroxide, potassiumhydroxide, potassium carbonate, sodium carbonate, and sodiumbicarbonate. The amount of pH adjuster or buffering material utilized inthe tobacco composition can vary, but is typically up to about 5 dryweight percent, and certain embodiments can be characterized by a pHadjuster/buffer content of at least about 0.5 dry weight percent, suchas about 1 to about 5 dry weight percent.

Exemplary colorants include various dyes and pigments, such as caramelcoloring and titanium dioxide. The amount of colorant utilized in thetobacco composition can vary, but is typically up to about 3 dry weightpercent, and certain embodiments are characterized by a colorant contentof at least about 0.1 dry weight percent, such as about 0.5 to about 3dry weight percent.

Exemplary humectants include glycerin and propylene glycol. The amountof humectant utilized in the tobacco composition can vary, but istypically up to about 2 dry weight percent, and certain embodiments canbe characterized by a humectant content of at least about 0.1 dry weightpercent, such as about 0.2 to about 2 dry weight percent.

Other ingredients such as preservatives (e.g., potassium sorbate) ordisintegration aids (e.g., microcrystalline cellulose, croscarmellosesodium, crospovidone, sodium starch glycolate, pregelatinized cornstarch, and the like) can also be used. Typically, such ingredients areused in amounts of up to about 10 dry weight percent and usually atleast about 0.1 dry weight percent, such as about 0.5 to about 10 dryweight percent.

Particularly with respect to smokeless tobacco compositions, tobaccocompositions comprising lipophilic active agent infused tobacco leavesand/or tobacco materials of the invention can be formed into desiredproduct shapes either before or after the infusion process. The methodand apparatus used to form the tobacco composition will depend on thedesired shape. Exemplary shapes include pill, tablet, sphere, sheet,coin, cube, bead, ovoid, obloid, bean, stick, and rod. For example, thetobacco composition can have the form of compressed tobacco pellets,multi-layered extruded pieces, extruded or formed rods or sticks,compositions having one type of tobacco formulation surrounded by adifferent type of tobacco formulation, rolls of tape-like films, readilywater-dissolvable or water-dispersible films or strips (see, forexample, U.S. Pat. Appl. Pub. No. 2006/0198873 to Chan et al.), orcapsule-like materials possessing an outer shell (e.g., a pliable orhard outer shell that can be clear, colorless, translucent or highlycolored in nature) and an inner region possessing tobacco or tobaccoflavor (e.g., a Newtoniam fluid or a thixotropic fluid incorporatingtobacco of some form).

Processed tobacco compositions comprising lipophilic active agentinfused tobacco leaves and/or tobacco materials of the invention, suchas compressed tobacco pellets, can be produced by compacting granulatedtobacco and associated formulation components in the form of a pellet,and optionally coating each pellet with an overcoat material. Exemplarygranulation devices are available as the FL-M Series granulatorequipment (e.g., FL-M-3) from Vector Corporation and as WP 120V and WP200VN from Alexanderwerk, Inc. Exemplary compaction devices, such ascompaction presses, are available as Colton 2216 and Colton 2247 fromVector Corporation and as 1200i, 2200i, 3200, 2090, 3090 and 4090 fromFette Compacting. Devices for providing outer coating layers tocompacted pelletized tobaccoformulations are available as CompuLab 24,CompuLab 36, Accela-Cota 48 and Accela-Cota 60 from Thomas Engineering.

Processed tobacco compositions comprising lipophilic active agentinfused tobacco leaves and/or tobacco materials of the invention, suchas multi-layered tobacco pellets, can be manufactured using a widevariety of extrusion techniques. For example, multi-layered tobaccopellets can be manufactured using co-extrusion techniques (e.g., using atwin screw extruder). In such a situation, successive wet or drycomponents or component mixtures can be placed within separate extrusionhoppers. Steam, gases (e.g., ammonia, air, carbon dioxide, and thelike), and humectants (e.g., glycerin or propylene glycol) can beinjected into the extruder barrel as each dry mix is propelled,plasticized, and cooked. As such, the various components are processedso as to be very well mixed, and hence, come in complete contact witheach other. For example, the contact of components is such thatindividual components can be well embedded in the extrusion matrix orextrudate. See, for example, U.S. Pat. No. 4,821,749 to Toft et al.,which is incorporated herein by reference. Multilayered materials canhave the general form of films, and alternatively, multi-layeredgenerally spherical materials can possess various layers extending fromthe inside outward.

Some shapes, such as rods or cubes, can be formed by first extruding thematerial through a die having the desired cross-section (e.g., round orsquare) and then optionally cutting the extruded material into desiredlengths. Exemplary extrusion equipment suitable for use in the inventioninclude industrial pasta extruders such as Model TP 200/300 availablefrom Emiliomiti, LLC of Italy. Sheet-like materials can be prepared byapplying the tobacco composition onto a moving belt and passing themoving belt through a nip formed by opposing rollers, followed bycutting the sheet into desired lengths.

Bioavailability

Bioavailability refers to the extent and rate at which the active moiety(drug or metabolite) enters systemic circulation, thereby accessing thesite of action. Bioavailability for a given formulation provides anestimate of the relative fraction of the orally administered dose thatis absorbed into the systemic circulation. Low bioavailability is mostcommon with oral dosage forms of poorly water-soluble, slowly absorbeddrugs. Insufficient time for absorption in the gastrointestinal tract isa common cause of low bioavailability. If the drug does not dissolvereadily or cannot penetrate the epithelial membrane (e.g., if it ishighly ionized and polar), time at the absorption site may beinsufficient. Orally administered drugs must pass through the intestinalwall and then the portal circulation to the liver, both of which arecommon sites of first-pass metabolism (metabolism that occurs before adrug reaches systemic circulation). Thus, many drugs may be metabolizedbefore adequate plasma concentrations are reached.

Bioavailability is usually assessed by determining the area under theplasma concentration-time curve (AUC). AUC is directly proportional tothe total amount of unchanged drug that reaches systemic circulation.Plasma drug concentration increases with extent of absorption; themaximum (peak) plasma concentration is reached when drug eliminationrate equals absorption rate. Peak time is the most widely used generalindex of absorption rate; the slower the absorption, the later the peaktime.

The bioavailability of some drugs is increased when co-administered withfood, particularly agents such as cannabinoids that are Class II drugsunder the Biopharmaceutical Drug Classification System (Kelepu et al.(2013) Acta Pharmaceutica Sinica B 3:361-372; Amidon et al. (1995)Pharm. Res. 12:413-420; Charman et al. (1997) J. Pharm. Sci. 86:269-282;Winstanley et al. (1989) Br. J. Clin. Pharmacol. 28:621-628). It is thelipid component of the food that plays a key role in the absorption oflipophilic drugs and that leads to enhanced oral bioavailability (Hunt &Knox (1968) 1 Physiol. 194:327-336; Kelepu et al. (2013) ActaPharmaceutica Sinica B 3:361-372). This has been attributed to theability of a high fat meal to stimulate biliary and pancreaticsecretions, to decrease metabolism and efflux activity, to increaseintestinal wall permeability, and to a prolongation of gastrointestinaltract (GIT) residence time and transport via the lymphatic system(Wagnera et al. (2001) Adv. Drug Del. Rev. 50:S13-31; Kelepu et al.(2013) Acta Pharmaceutica Sinica B 3:361-372). High fat meals alsoelevate triglyceride-rich lipoproteins that associate with drugmolecules and enhance intestinal lymphatic transport, which leads tochanges in drug disposition and changes the kinetics of thepharmacological actions of poorly soluble drugs (Gershkovich et al.(2007) Eur. J. Pharm. Sci. 32:24-32; Kelepu et al. (2013) ActaPharmaceutica Sinica B 3:361-372). However, co-administration of foodwith lipophilic drugs requires close control and/or monitoring of foodintake when dosing such drugs, and can also be subject to problems withpatient compliance (Kelepu et al. (2013) Acta Pharmaceutica Sinica B3:361-372).

In other aspects, the bioavailability enhancing agent within thecompositions and methods of the present invention is an edible oil orfat, a protective colloid, or both a protective colloid and an edibleoil or fat. In another aspect, the bioavailability enhancing agent isalso a lipophilic active agent taste masking agent. In anotherparticular aspect, where the bioavailability enhancing agent is both aprotective colloid, an edible oil or fat, and a lipophilic active agenttaste masking agent, the bioavailability enhancing agent is nonfat drymilk. In a further aspect, the bioavailability enhancing agent issubstantially free of omega-6 fatty acids. In other aspects, thebioavailability of the lipophilic active agent in a subject is at leastabout 1.5 times, 2 times, 5 times, or 10 times greater than thebioavailability of the lipophilic active agent in the subject in theabsence of the bioavailability enhancing agent. In a further aspect, thebioavailability of the lipophilic active agent in a subject is greaterthan 20%.

An edible oil is defined herein as an oil that is capable of undergoingde-esterification or hydrolysis in the presence of pancreatic lipase invivo under normal physiological conditions. Specifically, digestibleoils may be complete glycerol triesters of medium chain (C₇-C₁₃) or longchain (C₁₄-C₂₂) fatty acids with low molecular weight (up to C₆) mono-,di- or polyhydric alcohols. Some examples of digestible oils for use inthis invention thus include: vegetable, nut, or seed oils (such ascoconut oil, peanut oil, soybean oil, safflower seed oil, corn oil,olive oil, castor oil, cottonseed oil, arachis oil, sunflower seed oil,coconut oil, palm oil, rapeseed oil, evening primrose oil, grape seedoil, wheat germ oil, sesame oil, avocado oil, almond, borage, peppermintand apricot kernel oils) and animal oils (such as fish liver oil, sharkoil and mink oil).

In a further aspect, the bioavailability enhancing agent is a long chain(C₁₄-C₂₂) fatty acid. In a further aspect, the bioavailability enhancingagent is a medium chain (C₇-C₁₃) fatty acid. In further aspects, thebioavailability enhancing agent is a combination of medium and longchain fatty acids.

Examples of protective colloids include polypeptides (such as gelatin,casein, and caseinate), polysaccharides (such as starch, dextrin,dextran, pectin, and gum arabic), as well as whole milk, skimmed milk,milk powder or mixtures of these. However, it is also possible to usepolyvinyl alcohol, vinyl polymers, for example polyvinylpyrrolidone,(meth)acrylic acid polymers and copolymers, methylcellulose,carboxymethylcellulose, hydroxypropylcellulose and alginates. Forfurther details, reference may be made to R. A. Morton, Fast SolubleVitamins, Intern. Encyclopedia of Food and Nutrition, Vol. 9, PergamonPress 1970, pages 128-131.

Oral administration constitutes the preferred route of administrationfor a majority of drugs. However, drugs that have an undesirable orbitter taste leads to lack of patient compliance in the case of orallyadministered dosage forms. In such cases, taste masking is an essentialtool to improve patient compliance. Because lipophilic active agents(e.g., cannabinoids such as cannabidiol) have an undesirable tasteprofile, in order to improve compliance, the presently disclosedcompositions also comprise one or more lipophilic active agent tastemasking agents. Examples of lipophilic active agent taste-masking agentsinclude dry milk as described above, as well as menthol, sweeteners,sodium bicarbonate, ion-exchange resins, cyclodextrin inclusioncompounds, adsorbates, and the like.

In another aspect, taste-masking agents used with tobacco productsinclude flavoring agents such as salts (e.g., sodium chloride, potassiumchloride, sodium citrate, potassium citrate, sodium acetate, potassiumacetate, and the like), natural sweeteners (e.g., fructose, sucrose,glucose, maltose, mannose, galactose, lactose, and the like), artificialsweeteners (e.g., sucralose, saccharin, aspartame, acesulfame K,neotame, and the like); and mixtures thereof. In other aspects, suitableflavoring agents include, but are not limited to, vanilla, vanillin,ethyl vanillin, orange oil, peppermint oil, strawberry, raspberry, andmixtures thereof.

In a further aspect, the bioavailability enhancing agent issubstantially free of omega-6 fatty acids. As used herein,“substantially free” means largely but not wholly pure.

In other aspects, the bioavailability of the lipophilic active agent ina subject is at least about 1.5 times, 2 times, 2.5 times, 3 times, 3.5times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7times, 7.5 times, 8 times, 8.5 times, 9 times, 9.5 times, or 10 timesgreater than the bioavailability of the lipophilic active agent in thesubject in the absence of the bioavailability enhancing agent.

In a further aspect, the bioavailability of the lipophilic active agentin a subject is greater than 20% or at least about 21%, 22%, 23%, 24%,25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%,39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, or greater.

Assays and methods for measuring lipophilic active agent bioavailabilityare well known in the art (see, e.g., Rocci & Jusko (1983) Comput.Programs Biomed. 16:203-215; Shargel & Yu (1999) Appliedbiopharmaceutics & pharmacokinetics (4th ed.). New York: McGraw-Hill; Hu& Li (2011) Oral Bioavailability: Basic Principles, Advanced Concepts,and Applications, John Wiley & Sons Ltd.; Karschner et al. (2011)Clinical Chemistry 57:66-75; Ohlsson et al. (1980) Clin. Pharmacol.Ther. 28:409-416; Ohlsson et al. (1982) Biomed. Environ. Mass Spectrom.9:6-10; Ohlsson et al. (1986) Biomed. Environ. Mass Spectrom. 13:77-83;Karschner et al. (2010) Anal. Bioanal. Chem. 397:603-611).

Lyophilization

In a further aspect, the lipophilic active agent infused tobacco leavesand/or tobacco materials of the present invention are lyophilized.Lyophilization, also known as freeze-drying, is a process whereby wateris sublimed from a composition after it is frozen. The frozen solutionis then typically subjected to a primary drying step in which thetemperature is gradually raised under vacuum in a drying chamber toremove most of the water, and then to a secondary drying step typicallyat a higher temperature than employed in the primary drying step toremove the residual moisture in the lyophilized composition. Thelyophilized composition is then appropriately sealed and stored forlater use. Tang et al. (2004) Pharmaceutical Research 21:191-200describes the scientific principles pertaining to freeze drying andguidelines for designing suitable freeze drying processes. Furtherdescription of freeze drying is found in Remington (2006) The Scienceand Practice of Pharmacy, 21^(st) edition, Lippincott Williams &Wilkins, pp. 828-831.

Lipophilic Active Agents 1. Cannabinoids

Cannabis sativa L. is one of the most widely used plants for bothrecreational and medicinal purposes. Over 500 natural constituents havebeen isolated and identified from C. sativa covering several chemicalclasses (Ahmed et al. (2008) J. Nat. Prod. 71:536-542; Ahmed et al.(2008) Tetrahedron Lett. 49:6050-6053; ElSohly & Slade (2005) Life Sci.78:539-548; Radwan et al. (2009) J. Nat. Prod. 72:906-911; Radwan et al.(2008) Planta Medica. 74:267-272; Radwan et al. (2008) J. Nat. Prod.69:2627-2633; Ross et al. (1995) Zagazig J. Pharm. Sci. 4:1-10; Turneret al. (1980) J. Nat. Prod. 43:169-170). Cannabinoids belong to thechemical class of terpenophenolics, of which at least 85 have beenuniquely identified in Cannabis (Borgelt et al. (2013) Pharmacotherapy33:195-209).

Cannabinoids are ligands to cannabinoid receptors (CB₁, CB₂) found inthe human body (Pertwee (1997) Pharmacol. Ther. 74:129-180). Thecannabinoids are usually divided into the following groups: classicalcannabinoids; non-classical cannabinoids; aminoalkylindole-derivatives;and eicosanoids (Pertwee (1997) Pharmacol. Ther. 74:129-180). Classicalcannabinoids are those that have been isolated from C. sativa L. ortheir synthetic analogs. Non-classical cannabinoids are bi- ortri-cyclic analogs of tetrahydrocannabinol (THC) (without the pyranring). Aminoalkylindoles and eicosanoids are substantially different instructure compared to classical and non-classical cannabinoids. The mostcommon natural plant cannabinoids (phytocannabinoids) are cannabidiol(CBD), cannabigerol (CBG), cannabichromene (CBC), and cannabinol (CBN).The most psychoactive cannabinoid is Δ⁹-THC.

In recent years, marijuana and its components have been reported inscientific literature to counter the symptoms of a broad range ofconditions including but not limited to multiple sclerosis and otherforms of muscular spasm; movement disorders; pain, including migraineheadache; glaucoma; asthma; inflammation; insomnia; and high bloodpressure. There may also be utility for cannabinoids as anxiolytics,anti-convulsives, anti-depressants, anti-psychotics, anti-cancer agents,as well as appetite stimulants. Pharmacological and toxicologicalstudies of cannabinoids have largely been focused on a synthetic analogof Δ⁹-THC (commercially available under the generic name Dronabinol). In1985, Dronabinol was approved by the FDA for the treatment ofchemotherapy associated nausea and vomiting, and later forAIDS-associated wasting and anorexia.

Therapeutic use of cannabinoids has been hampered by the psychoactiveproperties of some compounds (e.g., Dronabinol) as well as their lowbioavailability when administered orally. Bioavailability refers to theextent and rate at which the active moiety (drug or metabolite) enterssystemic circulation, thereby accessing the site of action. The lowbioavailability of orally ingested cannabinoids (from about 6% to 20%;Adams & Martin (1996) Addiction 91: 1585-614; Agurell et al. (1986)Pharmacol. Rev. 38: 21-43; Grotenhermen (2003) Clin. Pharmacokinet. 42:327-60) has been attributed to their poor dissolution properties andextensive first pass metabolism.

Cannabinoids are a heteromorphic group of chemicals which directly orindirectly activate the body's cannabinoid receptors. There are threemain types of cannabinoids: herbal cannabinoids that occur uniquely inthe Cannabis plant, synthetic cannabinoids that are manufactured, andendogenous cannabinoids that are produced in vivo. Herbal cannabinoidsare nearly insoluble in water but soluble in lipids, alcohol, andnon-polar organic solvents. These natural cannabinoids are concentratedin a viscous resin that is produced in glandular structures known astrichomes. In addition to cannabinoids, the resin is rich in terpenes,which are largely responsible for the odor of the Cannabis plant.

The identification of Δ⁹-tetrahydrocannabinol (THC) as a majorpsychoactive drug and its chemical synthesis in 1964 opened a new era ofsynthetic cannabinoids as pharmacological agents. Cannabinoid researchhas increased tremendously in recent years since the discovery ofcannabinoid receptors and the endogenous ligands for these receptors.The receptors include CB1, predominantly expressed in the brain, andCB2, primarily found on the cells of the immune system. Cannabinoidreceptors belong to a superfamily of G-protein-coupled receptors. Theyare single polypeptides with seven transmembrane α-helices, and have anextracellular, glycosylated N-terminus and intracellular C-terminus.Both CB1 and CB2 cannabinoid receptors are linked to GI/O-proteins. Inaddition to these receptors, endogenous ligands for these receptorscapable of mimicking the pharmacological actions of THC have also beendiscovered. Such ligands were designated endocannabinoids and includedanandamide and 2-arachidonoyl glycerol (2-AG). Anandamide is produced inthe brain and peripheral immune tissues such as the spleen.

Unlike THC, which exerts its action by binding to CB1 and CB2,cannabidiol does not bind to these receptors and hence has nopsychotropic activity. Instead, cannabidiol indirectly stimulatesendogenous cannabinoid signaling by suppressing the enzyme that breaksdown anandamide (fatty acid amide hydroxylase, “FAAH”). Cannabidiol alsostimulates the release of 2-AG. Cannabidiol has been reported to haveimmunomodulating and anti-inflammatory properties, to exhibitanticonvulsive, anti-anxiety, and antipsychotic activity, and tofunction as an efficient neuroprotective antioxidant.

Cannabinoids in Cannabis are often inhaled via smoking, but may also beingested. Smoked or inhaled cannabinoids have reported bioavailabilitiesranging from 2-56%, with an average of about 30% (Huestis (2007) Chem.Biodivers. 4:1770-1804; McGilveray (2005) Pain Res. Manag. 10 Suppl.A:15A-22A). This variability is mainly due to differences in smokingdynamics. Cannabinoids that are absorbed through the mucous membranes inthe mouth (buccomucosal application) have bioavailabilities of around13% (Karschner et al. (2011) Clin. Chem. 57:66-75). By contrast, whencannabinoids are ingested, bioavailability is typically reduced to about6% (Karschner et al. (2011) Clin. Chem. 57:66-75).

Accordingly, in other aspects, within the compositions and methods ofthe present invention, the lipophilic active agent is a cannabinoid.

In particular aspects, at least one cannabinoid within the compositionsand methods of the present invention is selected from the groupconsisting of:

CBC Cannabichromene

V CBC Cannabichromenic acid

CBD Cannabidiol

A CBD Cannabidiolic acid

V CBD Cannabidivarin

CBG Cannabigerol

V CBG Cannabigerol propyl variant

CBL Cannabicyclol

CBN Cannabinol

V CBN Cannabinol propyl variant

CBO Cannabitriol

THC Tetrahydrocannabinol

A THC Tetrahydrocannabinolic acid

V THC Tetrahydrocannabivarin

VA THC Tetrahydrocannabivarinic acid

In particular aspects, at least one cannabinoid within the compositionsand methods of the present invention is a non-psychoactive cannabinoidsuch as cannabidiol. In some particularly disclosed aspects, thecannabinoid is selected from the group consisting of:

where A is aryl, and particularly

but not a pinene such as:

and the R₁-R₅ groups are each independently selected from the groups ofhydrogen, lower substituted or unsubstituted alkyl, substituted orunsubstituted carboxyl, substituted or unsubstituted alkoxy, substitutedor unsubstituted alcohol, and substituted or unsubstituted ethers, andR₆-R₇ are H or methyl. In particular aspects, there are no nitrogens inthe rings, and/or no amino substitutions on the rings.

In other aspects, the cannabinoid is selected from the group consistingof:

where there can be 0 to 3 double bonds on the A ring, as indicated bythe optional double bonds indicated by dashed lines on the A ring. The Cring is aromatic, and the B ring can be a pyran. Particular aspects aredibenzo pyrans and cyclohexenyl benzenediols. Particular aspects of thecannabinoids of the present invention may also be highly lipid soluble,and in particular aspects can be dissolved in an aqueous solution onlysparingly (for example 10 mg/ml or less). The octanol/water partitionratio at neutral pH in useful aspects is 5000 or greater, for example6000 or greater. This high lipid solubility enhances penetration of thedrug into the central nervous system (CNS), as reflected by its volumeof distribution (V_(d)) of 1.5 L/kg or more, for example 3.5 L/kg, 7L/kg, or ideally 10 L/kg or more, for example at least 20 L/kg.Particular aspects may also be highly water soluble derivatives that areable to penetrate the CNS, for example carboxyl derivatives.

R₇₋₁₈ are independently selected from the group of H, substituted orunsubstituted alkyl, especially lower alkyl, for example unsubstitutedC₁-C₃ alkyl, hydroxyl, alkoxy, especially lower alkoxy such as methoxyor ethoxy, substituted or unsubstituted alcohol, and unsubstituted orsubstituted carboxyl, for example COOH or COCH₃. In other aspects R₇₋₁₈can also be substituted or unsubstituted amino, and halogen.

In particular aspects, at least one cannabinoid within the compositionsand methods of the present invention is a non-psychoactive cannabinoid,meaning that the cannabinoid has substantially no psychoactive activitymediated by the cannabinoid receptor (for example an IC₅₀ at thecannabinoid receptor of greater than or equal to 300 nM, for examplegreater than 1 μM and a K_(i) greater than 250 nM, especially 500-1000nM, for example greater than 1000 nM).

In other particular aspects, the cannabinoids within the compositionsand methods of the present invention are selected from the groupconsisting of:

where R₁₉ is substituted or unsubstituted alkyl, such as lower alkyl(for example methyl), lower alcohol (such as methyl alcohol) or carboxyl(such as carboxylic acid) and oxygen (as in ═O); R₂₀ is hydrogen orhydroxy; R₂₁ is hydrogen, hydroxy, or methoxy; R₂₂ is hydrogen orhydroxy; R₂₃ is hydrogen or hydroxy; R₂₄ is hydrogen or hydroxy; R₂₅ ishydrogen or hydroxy; and R₂₆ is substituted or unsubstituted alkyl (forexample n-methyl alkyl), substituted or unsubstituted alcohol, orsubstituted or unsubstituted carboxy.

In other particular aspects, the cannabinoids within the compositionsand methods of the present invention are selected from the groupconsisting of:

wherein numbering conventions for each of the ring positions are shown,and R₂₇, R₂₈ and R₂₉ are independently selected from the groupconsisting of H, unsubstituted lower alkyl such as CH₃, and carboxylsuch as COCH₃. Particular examples of nonpsychoactive cannabinoids thatfall within this definition are cannabidiol and

and other structural analogs of cannabidiol.

In other particular aspects, the cannabinoids within the compositionsand methods of the present invention are selected from the groupconsisting of:

wherein R₂₇, R₂₈ and R₂₉ are independently selected from the groupconsisting of H, lower alkyl such as CH₃, and carboxyl such as COCH₃,and particularly wherein:

-   -   a) R₂₇═R₂₈═R₂₉═H    -   b) R₂₇═R₂₉═H; R₂₈—CH₃    -   c) R₂₇═R₂₈═CH₃; R₂₉═H    -   d) R₂₇═R₂₈═COCH₃; R₂₉═H    -   e) R₂₇═H; R₂₈═R₂₉═COCH₃

When R₂₇═R₂₈=R₂₉═H, then the compound is cannabidiol (CBD). WhenR₂₇═R₂₉═H and R₂₈═CH₃, the compound is CBD monomethyl ether. WhenR₂₇═R₂₈═CH₃ and R₂₉═H, the compound is CBD dimethyl ether. WhenR₂₇═R₂₈═COCH₃ and R₂₉═H, the compound is CBD diacetate. When R₂₇═H andR₂₈═R₂₉═COCH₃, the compound is CBD monoacetate.

2. Terpenes and Terpenoids

Terpenes are a diverse group of organic hydrocarbons derived from5-carbon isoprene units and are produced by a wide variety of plants.Terpenoids are terpenes which have been chemically modified to addfunctional groups including heteroatoms. Terpenes and terpenoids areimportant building blocks for hormones, vitamins, pigments, steroids,resins, and essential oils. Terpenes are naturally present in Cannabis;however, they can be removed during the extraction process. Terpenes andterpenoids have various pharmaceutical (pharmacodynamic) effects and canbe selected for the desired pharmaceutical activities.

In one embodiment, the terpene/terpenoid includes limonene. Limonene isa colorless liquid hydrocarbon classified as a cyclic terpene. The morecommon D-isomer possesses a strong smell of oranges and a bitter taste.It is used in chemical synthesis as a precursor to carvone and as asolvent in cleaning products. Limonene is a chiral molecule. Biologicalsources produce one enantiomer—the principal industrial source—citrusfruit, contains D-limonene ((+)-limonene), which is the (R)-enantiomer(CAS number 5989-27-5, EINECS number 227-813-5). Racemic limonene isknown as dipentene. Its IUPAC name is1-methyl-4-(1-methylethenyl)-cyclohexene. It is also known as4-isopropenyl-1-methylcyclohexenep-Menth-1,8-dieneRacemic: DL-limonene;dipentene.

Limonene has a history of use in medicine, food and perfume. It has verylow toxicity, and humans are rarely allergic to it. Limonene is used asa treatment for gastric reflux and as an anti-fungal agent. Its abilityto permeate proteins makes it a useful treatment for toenail fungus.Limonene is also used for treating depression and anxiety. Limonene isreported to assist in the absorption of other terpenoids and chemicalsthrough the skin, mucous membranes and digestive tract. Limonene hasimmunostimulant properties. Limonene is also used as botanicalinsecticide

The principle metabolites of limonene are (+)- and (−)-trans-carveol, aproduct of 6-hydroxylation) and (+)- and (−)-perillyl alcohol, a productof 7-hydroxylation by CYP2C9 and CYP2C19 cytochromes in human livermicrosomes. The enantiomers of perillyl alcohol have been researched forpossible pharmacological possibilities as dietary chemotherapeuticagents. They are considered novel therapeutic options in some CNSneoplasms and other solid tumors, especially for treatment of gliomas.The cytotoxic activities of perillyl alcohol and limonene metabolitesare likely due to their antiangiogenic properties, hyperthermia inducingeffects, negative apoptosis regulation and effect on Ras pathways.

In another embodiment, the terpene/terpenoid includes linalool. Linaloolis a naturally occurring terpene alcohol chemical found in many flowersand spice plants with many commercial applications, the majority ofwhich are based on its pleasant scent (floral and slightly spicy). It isalso known as β-linalool, linalyl alcohol, linaloyl oxide, p-linalool,allo-ocimenol, and 3,7-dimethyl-1,6-octadien-3-ol. Its IUPAC name is3,7-dimethylocta-1,6-dien-3-ol.

More than 200 species of plants produce linalool, mainly in the familiesLamiaceae, Lauraceae and Rutaceae. It has also been found in some fungi.Linalool has been used for thousands of years as a sleep aid. Linaloolis an important precursor in the formation of Vitamin E. It has ahistory of use in the treatment of both psychosis and anxiety, and as ananti-epileptic agent. It also provides analgesic pain relief. Its vaporshave been shown to be an effective insecticide against fleas, fruitflies and cockroaches. Linalool is used as a scent in an estimated60-80% of perfumed hygiene products and cleaning agents including soaps,detergents, shampoos and lotions.

In another embodiment, the terpene/terpenoid includes myrcene. Myrcene,or β-myrcene, is an olefinic natural organic compound. It is classifiedas a hydrocarbon, more precisely as a monoterpene. Terpenes are dimersof isoprene, and myrcene is one of the most important. Myrcene is acomponent of the essential oil of several plants including bay,Cannabis, ylang-ylang, wild thyme, mango, parsley and hops. Myrcene isproduced mainly semi-synthetically from myrcia, from which it gets itsname. Myrcene is a key intermediate in the production of severalfragrances. α-Myrcene is the name for the structural isomer2-methyl-6-methylene-1,7-octadiene, which is not found in nature and islittle used. Its IUPAC name is 7-methyl-3-methylene-1,6-octadiene.

Myrcene has an analgesic effect and is likely to be responsible for themedicinal properties of lemon grass tea. It has anti-inflammatoryproperties through Prostaglandin E2. The analgesic action can be blockedby naloxone or yohimbine in mice, which suggests mediation by alpha2-adrenoceptor stimulated release of endogenous opioids. β-Myrcene isreported to have anti-inflammatory properties, and is used to treatspasms, sleep disorders and pain. Myrcene appears to lower resistanceacross the blood to brain barrier, allowing itself and many otherchemicals to cross the barrier more effectively.

In another embodiment, the terpene/terpenoid includes α-Pinene. α-Pineneis one of the primary monoterpenes that is physiologically critical inboth plants and animals. It is an alkene and it contains a reactivefour-membered ring. α-Pinene tends to react with other chemicals,forming a variety of other terpenes including D-limonene and othercompounds. α-Pinene has been used for centuries as a bronchodilator inthe treatment of asthma. It is highly bioavailable with 60% humanpulmonary uptake with rapid metabolism. α-Pinene is an anti-inflammatoryvia PGE1, and appears to be a broad-spectrum antibiotic. It acts as anacetylcholinesterase inhibitor, aiding memory. Products of α-pinenewhich have been identified include pinonaldehyde, norpinonaldehyde,pinic acid, pinonic acid, and pinalic acid.

Pinene is found in conifer, pine and orange. α-Pinene is a majorconstituent in turpentine. Its IUPAC name is(1S,5S)-2,6,6-Trimethylbicyclo[3.1.1]hept-2-ene ((−)-α-Pinene).

In another embodiment, the terpene/terpenoid includes β-Pinene. β-Pineneis one of the most abundant compounds released by trees. It is one ofthe two isomers of pinene, the other being α-pinene. It is a commonmonoterpene, and if oxidized in air, the allylic products of thepinocarveol and myrtenol family prevail. Its IUPAC name is6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane and is also known as2(10)-Pinene; Nopinene; Pseudopinene. It is found in cumin, lemon, pineand other plants.

In another embodiment, the terpene/terpenoid includes caryophyllene,also known as β-caryophyllene. Caryophyllene is a natural bicyclicsesquiterpene that is a constituent of many essential oils, includingclove, Cannabis, rosemary and hops. It is usually found as a mixturewith isocaryophyllene (the cis double bond isomer) and α-humulene, aring-opened isomer. Caryophyllene is notable for having a rarecyclobutane ring. Its IUPAC name is4,11,11-trimethyl-8-methylene-bicyclo[7.2.0]undec-4-ene.

Caryophyllene is known to be one of the compounds that contribute to thespiciness of black pepper. In a study conducted by the Swiss FederalInstitute of Technology, β-caryophyllene was shown to be selectiveagonist of cannabinoid receptor type-2 (CB2) and to exert significantcannabimimetic, anti-inflammatory effects in mice. Anti-nociceptive,neuroprotective, anxiolytic, antidepressant and anti-alcoholic activityhave been tied to caryophyllene. Because β-caryophyllene is an FDAapproved food additive, it is considered the first dietary cannabinoid.

In another embodiment, the terpene/terpenoid includes citral. Citral, or3,7-dimethyl-2,6-octadienal or lemonal, is either a pair, or a mixtureof terpenoids with the molecular formula C₁₀H₁₆O. The two compounds aredouble bond isomers. The E-isomer is known as geranial or citral A. TheZ-isomer is known as neral or citral B. Its IUPAC name is3,7-dimethylocta-2,6-dienal. It is also known as citral, geranial,neral, geranialdehyde.

Citral is present in the oils of several plants, including lemon myrtle,lemongrass, verbena, lime, lemon and orange. Geranial has a pronouncedlemon odor. Neral's lemon odor is not as intense, but sweet. Citral isprimarily used in perfumery for its citrus quality. Citral is also usedas a flavor and for fortifying lemon oil. It has strong antimicrobialqualities, and pheromonal effects in insects. Citral is used in thesynthesis of vitamin A, ionone and methylionone.

In another embodiment, the terpene/terpenoid includes humulene.Humulene, also known as α-humulene or α-caryophyllene, is a naturallyoccurring monocyclic sesquiterpene (C₁₅H₂₄), which is an 11-memberedring consisting of 3 isoprene units containing three nonconjugated C═Cdouble bonds, two of them being triply substituted and one being doublysubstituted. It was first found in the essential oils of Humulus lupulus(hops). Humulene is an isomer of β-caryophyllene, and the two are oftenfound together as a mixture in many aromatic plants.

Humulene has been shown to produce anti-inflammatory effects in mammals,which demonstrates potential for management of inflammatory diseases. Itproduces similar effects to dexamethasone, and was found to decrease theedema formation caused by histamine injections. Humulene producedinhibitory effects on tumor necrosis factor-α (TNFα) andinterleukin-1.beta. (IL1B) generation in carrageenan-injected rats. InChinese medicine, it is blended with β-caryophyllene and used as aremedy for inflammation.

Other exemplary terpenes and terpenoids include menthol, eucalyptol,borneol, pulegone, sabinene, terpineol, and thymol. In one embodiment,an exemplary terpene/terpenoid is eucalyptol.

3. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs are the second-largest category of pain management treatmentoptions in the world. The global pain management market was estimated at$22 billion in 2011, with $5.4 billion of this market being served byNSAID's. The U.S. makes up over one-half of the global market. Theopioids market (such as morphine) form the largest single painmanagement sector but are known to be associated with serious dependenceand tolerance issues.

Although NSAIDs are generally a safe and effective treatment method forpain, they have been associated with a number of gastrointestinalproblems including dyspepsia and gastric bleeding.

Delivery of NSAIDs through the compositions and methods of the presentinvention will provide the beneficial properties of pain relief withlessened negative gastrointestinal effects, and also deliver lowerdosages of active ingredients in order to provide pain managementoutcomes across a variety of indications.

Accordingly, in other aspects, within the compositions and methods ofthe present invention, the lipophilic active agent is an NSAID,particularly wherein the NSAID is selected from the group consisting ofacetylsalicylic acid, ibuprophen, acetaminophen, diclofenac,indomethacin, and piroxicam.

4. Vitamins

The global vitamin and supplement market is worth $68 billion accordingto Euromonitor. The category is both broad and deep, comprised of manypopular and some lesser known substances. Vitamins in general arethought to be an $8.5 billion annual market in the U.S. The U.S. is thelargest single national market in the world, and China and Japan are the2^(nd) and 3^(rd) largest vitamin markets.

Vitamin E is fat soluble and can be incorporated into cell membraneswhich can protect them from oxidative damage. Global consumption ofnatural source vitamin E was 10,900 metric tons in 2013 worth $611.9million.

Delivery of fat soluble vitamins through the compositions and methods ofthe present invention will result in less waste and lower dosages ofadministration. In addition, ingestion of pills is an unpleasantexperience for many people so vitamin delivery through common foodgroups will vastly expand demand and use.

Accordingly, in other aspects, within the compositions and methods ofthe present invention, the lipophilic active agent is a vitamin,particularly wherein the vitamin is vitamin E.

5. Nicotine Compounds

Nicotine is a natural ingredient in tobacco leaves where it acts as abotanical insecticide (Hukkanen et al. (2005) Pharmacological Reviews57:79-115). Comprising about 95% of the total alkaloid content ofcommercial cigarette tobacco, nicotine comprises about 1.5% by weight ofcommercial cigarette tobacco (Hukkanen et al. (2005) PharmacologicalReviews 57:79-115). Although oral snuff and pipe tobacco containconcentrations of nicotine similar to cigarette tobacco, cigar andchewing tobacco typically contain only about half of the nicotineconcentration of cigarette tobacco (Hukkanen et al. (2005)Pharmacological Reviews 57:79-115). An average tobacco rod typicallycontains 10 to 14 mg of nicotine (Hukkanen et al. (2005) PharmacologicalReviews 57:79-115), and on average about 1 to 1.5 mg of nicotine isabsorbed systemically during smoking (Hukkanen et al. (2005)Pharmacological Reviews 57:79-115). The nicotine in tobacco is largelythe levorotary (S)-isomer, only 0.1 to 0.6% of total nicotine content is(R)-nicotine (Hukkanen et al. (2005) Pharmacological Reviews 57:79-115).The (R)-nicotine content of tobacco smoke is higher, with up to 10% ofnicotine in smoke reported to be (R)-isomer, and thought to beattributed to racemization occurring during combustion (Hukkanen et al.(2005) Pharmacological Reviews 57:79-115).

More than 99% of all nicotine that is consumed worldwide is deliveredthrough smoking cigarettes. Approximately 6,000,000 deaths per year,worldwide, are attributed primarily to the delivery of nicotine throughthe act of smoking according to the Centers for Disease Control andPrevention, which also estimates that over $170 billion per year isspent just in the U.S. on direct medical care costs for adult smokers.In any twelve month period, 69% of U.S. adult smokers want to quitsmoking and 43% of U.S. adult smokers have attempted to quit.

Worldwide, retail cigarette sales were worth $722 billion in 2013, withover 5.7 trillion cigarettes sold to more than 1 billion smokers. Itwould be desirable in the art to provide further methods for alteringthe character and nature of tobacco (and tobacco compositions andformulations) useful in smoking articles and/or or smokeless tobaccoproducts, including enhancement of bioavailability of active agents,masking of unpleasant tastes, and the incorporation of additional activeagents. Furthermore, the delivery of nicotine to satisfy current demandvia the compositions and methods of the present invention, can in partalleviate the consumer demand for cigarettes. Since most of the adversehealth outcomes of nicotine consumption are associated with the deliverymethod and only to a lesser degree to the actual ingestion of nicotine,a vast positive community health outcome can be achieved through thereduction in smoking cigarettes.

Accordingly, in other aspects, within the compositions and methods ofthe present invention, the lipophilic active agent is a nicotinecompound. Tobacco alkaloids include nicotine and nicotine-like orrelated pharmacologically active compounds such as nor-nicotine,lobeline and the like, as well as the free base substance nicotine andall pharmacologically acceptable salts of nicotine, including acidaddition salts. “Nicotine compounds” as that term is used hereintherefore includes all the foregoing tobacco alkaloids, as well asnicotine salts including but not limited to nicotine hydrogen tartrateand nicotine bitartrate dihydrate, as well as nicotine hydrochloride,nicotine dihydrochloride, nicotine sulfate, nicotine citrate, nicotinezinc chloride monohydrate, nicotine salicylate, nicotine oil, nicotinecomplexed with cyclodextrin, polymer resins such as nicotine polacrilex,nicotine resinate, and other nicotine-ion exchange resins, either aloneor in combination. The nicotine compounds also include nicotine analogsthat include, but are not limited to the structures shown below for(s)-Nicotine, Nornicotine, (S)-Cotinine, B-Nicotyrine,(S)-Nicotene-N′-Oxide, Anabasine, Anatabine, Myosmine, B-Nornicotyrine,4-(Methylamino)-1-(3-pyridyl)-1-butene (Metanicotine) cis or trans,N′-Methylanabasine, N′Methylanatabine, N′Methylmyosmine,4-(Methylamino)-1-(3-pyridyl)-1-butanone (Pseudoxynicotine), and2,3′-Bipyridyl (Hukkanen et al. (2005) Pharmacological Reviews57:79-115):

The nicotine compound may be used in one or more distinct physical formswell known in the art, including free base forms, encapsulated forms,ionized forms and spray-dried forms.

For additional description regarding the chemistry, absorption,metabolism, kinetics and biomarkers of nicotine is described in Hukkanenet al. (2005) Pharmacological Reviews 57:79-115 and Benowitz et al.(2009) Handb. Exp. Pharmacol. 192:29-60, which are both attached asAppendix C and incorporated herein in their entireties.

6. Phosphodiesterase Type 5 Inhibitors

Phosphodiesterase type 5 inhibitors (PDE5 inhibitors) block thedegradative action of cGMP-specific phosphodiesterase type 5 (PDE5) oncyclic GMP in the smooth muscle cells lining the blood vessels supplyingthe corpus cavernosum of the penis. These drugs, including vardenafil(Levitra®), sildenafil (Viagra®), and tadalafil (Cialis®), areadministered orally for the treatment of erectile dysfunction and werethe first effective oral treatment available for the condition.

PDE5 inhibitors have also been studied for other clinical use as well,including cardiovascular and heart diseases. For example, because PDE5is also present in the arterial wall smooth muscle within the lungs,PDE5 inhibitors have also been explored for lung diseases such aspulmonary hypertension and cystic fibrosis. Pulmonary arterialhypertension, a disease characterized by sustained elevations ofpulmonary artery pressure, which leads to an increased incidence offailure of the right ventricle of the heart, which in turn can result inthe blood vessels in the lungs become overloaded with fluid. Two oralPDE5 inhibitors, sildenafil (Revatio®) and tadalafil (Adcirca®), areapproved for the treatment of pulmonary arterial hypertension. PDE5inhibitors have been found to have activity as both a corrector andpotentiator of CFTR protein abnormalities in animal models of cysticfibrosis disease (Lubamba et al., Am. J. Respir. Crit. Care Med. (2008)177:506-515, Lubamba et al., J. Cystic Fibrosis (2012) 11:266-273).Sildenafil has also been studied as a potential anti-inflammatorytreatment for cystic fibrosis. Oral PDE5 inhibitors have also beenreported to have anti-remodeling properties and to improve cardiacinotropism, independent of afterload changes, with a good safety profile(Giannetta et al., BMC Medicine (2014) 12:185). However, oraladministration of PDE5 inhibitors results in poor and variablebioavailability and also extensive metabolism in the liver (Sandqvist etal., Eur. J. Clin. Pharmacol. (2013) 69:197-207; Mehrotra, Intl. J.Impotence Res. (2007) 19:253-264). If oral doses are increased beyondcertain levels, the incidence of systemic side effects increase whichprevents the acceptable use of these drugs. (Levitra EMEA ScientificDiscussion Document, 2005).

Accordingly, in other aspects, within the compositions and methods ofthe present invention, the PDE5 inhibitor may include, but is notlimited to, avanafil, lodenafil, mirodenafil, sildenafil (or analogsthereof, for example, actetildenafil, hydroxyacetildenafil, ordimethyl-sildenafil), tadalafil, vardenafil, udenafil, acetildenafil, orthiome-thisosildenafil. The structures of these compounds arerespectively shown below:

7. Maca Extract

Lepidium meyenii (Maca, maca-maca, maino, ayak chichira, and ayakwillku) is a Peruvian plant of the Brassicaceae family cultivated formore than 2000 years. Its main active principles are alkaloids(Macaridine, Lepidiline A and B); bencil-isotiocyanate andglucosinolates; macamides, beta-ecdysone and fitosterols. Thesesubstances activate ATP synthesis which confers energizing properties.They also diminish variations in homeostasis produced by stress becausethey reduce corticosterone's high levels; prevent glucose diminution andthe increase of suprarenal glands' weight due to stress. They alsorestore homeostasis and improve energy (Lopez-Fando et al. (2004)Phytother Res. 18:471-4). A double blind placebo-controlled, randomized,parallel trial study in which active treatment with different doses ofLepidium meyenii was compared with placebo showed an improvement insexual desire. (Gonzales et al. (2002) Andrologia 34:367-72). Lepidiummeyenii also improves sperm production and sperm motility by mechanismsnot related to LH, FSH, PRL, T and E2 (Gonzales et al. (2001) Asian J.Androl. 3:301-3).

8. Estrogen

As used herein, “estrogen” includes estrogenic steroids such asestradiol (17-β-estradiol), estradiol benzoate, estradiol 17β-cypionate, estropipate, equilenin, equilin, estriol, estrone, ethinylestradiol, conjugated estrogens, esterified estrogens, and mixturesthereof.

Estrogens refer to a group of endogenous and synthetic hormones that areimportant for and used for tissue and bone maintenance. Estrogens areendocrine regulators in the cellular processes involved in thedevelopment and maintenance of the reproductive system. The role ofestrogens in reproductive biology, the prevention of postmenopausal hotflashes, and the prevention of postmenopausal osteoporosis are wellestablished. Estradiol is the principal endogenous human estrogen, andis found in both women and men.

The biological actions of estrogens and antiestrogens are manifestthrough two distinct intracellular receptors, estrogen receptor alpha(ERα) and estrogen receptor beta (ERβ). Endogenous estrogens aretypically potent activators of both receptor subtypes. For exampleestradiol acts as an ERα agonist in many tissues, including breast,bone, cardiovascular and central nervous system tissues. Selectiveestrogen receptor modulators commonly act differently in differenttissues. For example, a SERM may be an ERα antagonist in the breast, butmay be a partial ERα agonist in the uterus, bone and cardiovascularsystems. Compounds that act as estrogen receptor ligands are, therefore,useful in treating a variety of conditions and disorders.

9. Progesterone and Progestins

The term “progesterone” as used herein refers to a member of theprogestin family and comprises a 21 carbon steroid hormone. Progesteroneis also known as D4-pregnene-3,20-dione; 4-pregnene-3,20-dione; orpregn-4-ene-3,20-dione. A progestin is a molecule whose structure isrelated to that of progesterone, is synthetically derived, and retainsthe biologically activity of progesterone. Representative syntheticprogestin include, but are not limited to, modifications that produce17a-OH esters (i.e., 17 a-hydroxyprogesterone caproate), as well as,modifications that introduce 6 a-methyl, 6-Me, 6-ene, and 6-chlorosubstituents onto progesterone (i.e., medroxyprogesterone acetate,megestrol acetate, and chlomadinone acetate).

10. Testosterone

Testosterone is the main androgenic hormone formed in the testes.Testosterone therapy is currently indicated for the treatment of malehypogonadism. It is also under investigation for the treatment ofwasting conditions associated with AIDS and cancer, testosteronereplacement in men over the age of 60, osteoporosis, combination hormonereplacement therapy for women and male fertility control.

Orally administered testosterone is largely degraded in the liver, andis therefore not a viable option for hormone replacement since it doesnot allow testosterone to reach systemic circulation. Further, analoguesof testosterone modified to reduce degradation (e.g., methyltestosteroneand methandrostenolone) have been associated with abnormalities in liverfunction, such as elevation of liver enzymes and conjugated bilirubin.Injected testosterone produces wide peak-to-trough variations intestosterone concentrations that do not mimic the normal fluctuations oftestosterone, and makes maintenance of physiological levels in theplasma difficult. Testosterone injections are also associated with moodswings and increased serum lipid levels. Injections require largeneedles for intramuscular delivery, which leads to diminished patientcompliance due to discomfort.

To overcome these problems, transdermal delivery approaches have beendeveloped to achieve therapeutic effects in a more patient friendlymanner. For example, U.S. Pat. No. 5,460,820 discloses atestosterone-delivering patch for delivering 50 to 500 μg/day oftestosterone to a woman. In addition, U.S. Pat. No. 5,152,997 disclosesa device comprising a reservoir of testosterone with a skin permeationenhancer and a means for maintaining the reservoir in diffusionalcommunication with the skin, such as an adhesive carrier device or abasal adhesive layer.

11. Fentanyl

Fentanyl (also known as fentanil) is a potent synthetic narcoticanalgesic with a rapid onset and short duration of action. Fentanyl is astrong agonist at μ-opioid receptors. Fentanyl is manufactured under thetrade names of SUBLIMAZE, ACTIQ, DUROGESIC, DURAGESIC, FENTORA, ONSOLISINSTANYL, ABSTRAL, and others. Historically, fentanyl has been used totreat chronic breakthrough pain and is commonly used before proceduresas an anesthetic in combination with a benzodiazepine. Fentanyl isapproximately 100 times more potent than morphine with 100 micrograms offentanyl approximately equivalent to 10 mg of morphine and 75 mg ofpethidine (meperidine) in analgesic activity.

Suitable analogues of fentanyl include, without limitation, thefollowing: alfentanil (trade name ALFENTA), an ultra-short-acting (fiveto ten minutes) analgesic; sufentanil (trade name SUFENTA), a potentanalgesic for use in specific surgeries and surgery in heavilyopioid-tolerant/opioid-dependent patients; remifentanil (trade nameULTIVA), currently the shortest-acting opioid, has the benefit of rapidoffset, even after prolonged infusions; carfentanil (trade name WILDNIL)an analogue of fentanyl with an analgesic potency 10,000 times that ofmorphine and is used in veterinary practice to immobilize certain largeanimals such as elephants; and lofentanil an analogue of fentanyl with apotency slightly greater than carfentanil.

12. Buprenorphine

Buprenorphine(17-(cyclopropyl-methyl)-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihy-dro-3-hydroxy-6-methoxy-α-methyl-6,14-ethenomorphinan-7-methanol)is an endoethylene morphinan derivative and a partial agonist ofμ-opioid receptors with a strong analgesic effect. Buprenorphine is apartially synthetic opiate whose advantage over other compounds fromthis class of substance lies in a higher activity. This means thatfreedom from pain can be achieved in cancer or tumour patients with veryunfavourable diagnosis, in the final stage, with daily doses of around 1mg. A feature of buprenorphine in this context over the synthetic opioidfentanyl and its analogues is that the addictive potential ofbuprenorphine is lower than that of these compounds. A disadvantage isthat, owing to the high molecular weight of buprenorphine, namely 467.64daltons, it has been traditionally been difficult to effect itstransdermal absorption.

13. Scopolamine

Scopolamine is a so-called antiemitic, it is preferably used to avoidnausea and vomiting, for example, arising from repeated passive changesin the balance occurring during traveling. Scopolamine is represented bythe following chemical structure:

Scopolamine analogs are also encompassed by the compositions and methodsof the present invention. It is understood that the phrase “scopolamineanalogs” includes compounds that generally have the same backbone asscopolamine, but where various moieties have been substituted orreplaced by other substituents or moieties. Some examples of scopolamineanalogs that can be used in the compositions and methods disclosedherein include, but are not limited to, salts of scopolamine withvarious acids, such as hydrochloric acid, hydrobromic acid, hydroiodicacid, nitric acid, phosphoric acid, sulfuric acid, and the like. In oneaspect, a suitable scopolamine analog can be scopolamine hydrobromide.

Additional examples of scopolamine analogs include, but are not limitedto, N-alkylated analogs of scopolamine, that is, analogs containing analkyl substituent attached to the nitrogen atom, forming a quaternaryammonium species. By “alkyl” is meant a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl,octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.The alkyl group can also be substituted or unsubstituted.

Also included are other salts (e.g., pharmaceutically acceptable salts)of such N-alkylated scopolamine analogs.

Still further examples of scopolamine analogs include, but are notlimited to, un-epoxylated analogs of scopolamine, that is, analogs wherethe epoxy group is removed. One example of such an analog is atropine.Like scopolamine, atropine has various salt and N-alkylated analogs.These atropine analogs are intended to be included by the phrase“scopolamine analogs.” As such, further examples of scopolamine analogsinclude, but are not limited to, analogs of atropine with various salts(e.g., atropine hydrobromide, atropine hydrochloride, and the like) andN-alkylated analogs of atropine (e.g., atropine methyl bromide). Alsoincluded are homatropine and its salts and N-alkylated analogs.

A list of suitable scopolamine analogs that can be used in the disclosedcompositions and methods, including their commercial brand names,includes, but is not limited to, atropine, atropine hydrobromide,atropine oxide hydrochloride, atropine sulfate, belladonna, scopolamine,scopolamine hydrobromide, scopolamine methylbromide, scopolaminebutylbromide, homatropine, ipratropium, tiotropium, hyoscyamine sulfate,methscopolamine, methscopolamine bromide, homatropine hydrobromide,homatropine methylbromide, hyoscyamine, hyoscyamine hydrobromide,hyoscyamine sulfate, propantheline bromide, anisotropine, anisotropinemethylbromide, methantheline bromide, emepronium bromide, clindinium,clidinium bromide, hyoscine, hyoscine butylbromide, hyoscinehydrobromide, hyoscine methobromide, hyoscine methonitrite, hyoscyamine,hyoscyamine sulfate, buscapine, buscolysin, buscopan, butyiscopolamine,hyoscine N-butylbromide, N-butylscopolammonium bromide, scopolanbromide, butylscopolammonium bromide, N-butylscopolammonium chloride,hyoscine N-butylbromide, DD-234, hyoscine methiodide, hyoscinemethobromide, methyiscopolamine nitrate, methylscopolammoium methylsulfate, N-methylscine methyl sulfate, N-methyl scopolamine bromide,N-methylscopolamine iodide, N-methyl scopolamine methylchloride,N-methylscopolamine methylsulfate, N-methylscopolamine nitrate, skopyl,ulix bromide, N-methyl scopolamine, N-methyl scopolamine methobromide,scopolamine methylchloride, N-methylscine methylsulfate, tematropiummethylsulfate, and N-isopropylatropine, including salts and derivativesthereof.

Process

In other aspects, a process for making lipophilic active agent infusedtobacco leaves and/or tobacco materials is provided comprising the stepsof:

-   -   (a) contacting tobacco leaves and/or tobacco materials with an        oil comprising a lipophilic active agent and a bioavailability        enhancing agent, wherein the bioavailability enhancing agent        comprises an edible oil comprising long chain fatty acids; and    -   (b) dehydrating the tobacco leaves and/or tobacco materials;    -   thereby producing lipophilic active agent infused tobacco leaves        and/or tobacco materials;    -   wherein the lipophilic active agent infused tobacco leaves        and/or tobacco materials comprise a therapeutically effective        amount of the lipophilic active agent, and further wherein:    -   (i) the lipophilic active agent is selected from the group        consisting of cannabinoids, terpenes and terpenoids, NSAIDs,        vitamins, nicotine compounds, phosphodiesterase type 5 (PDE5)        inhibitors, Maca extract, estrogen, progestin, testosterone,        buprenorphine, and scopolamine; and    -   (ii) the bioavailability enhancing agent enhances the        bioavailability of the lipophilic active agent.

In another aspect, step (a) further comprises saturating the foodproduct in the oil comprising the lipophilic active agent and thebioavailability enhancing agent. In another aspect, step (a) furthercomprises contacting the tobacco leaves and/or tobacco materials with aflavoring agent, particularly wherein the flavoring agent is selectedfrom the group consisting of vanilla, vanillin, ethyl vanillin, orangeoil, peppermint oil, strawberry, raspberry, and mixtures thereof. Inanother aspect, the process further comprises a step of lyophilizing thelipophilic active agent infused tobacco leaves and/or tobacco materials.

In further aspects, the disclosed processes and methods use dehydrationmethods using dielectric energy, particularly microwave energy. In someaspects, the dielectric energy is selected from the group consisting ofradio frequency energy, low frequency microwave energy, and highfrequency microwave energy. In some aspects, the dehydration methodsfurther comprise using dielectric energy under vacuum. In still furtheraspects, the dehydration methods further comprise stirring at atemperature of less than 70° C. In still further aspects, the disclosedprocesses and methods use dehydration methods using spray dryingtechnology (e.g., methods of producing dry powders from a liquid orslurry by rapidly drying with a hot gas; see generally Mujumdar (2007)Handbook of Industrial Drying, CRC Press).

Methods of Treatment

In a further aspect, a method of treating a condition is provided,comprising administering any of the compositions disclosed herein to asubject in need thereof.

The active agents of the present invention are effective over a widedosage range. For example, in treating adult humans, compositions andmethods of the present invention comprise dosages of lipophilic activeagents from 0.01 mg to 1,000 mg, from 0.5 mg to 500 mg, from 1 mg to 100mg, from 5 mg to 50 mg, and from 10 mg to 25 mg. Alternatively, intreating adult humans, compositions and methods of the present inventioncomprise dosages of lipophilic active agents of 0.01 mg, 0.05 mg, 0.1mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg,400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg,850 mg, 900 mg, 950 mg, or 1,000 mg.

In one aspect, where the lipophilic active agent within the compositionsand methods of the invention is a cannabinoid, the condition is selectedfrom the group consisting of cardiac diseases such as heart disease,ischemic infarcts, and cardiometabolic disorders; neurological diseasessuch as Alzheimer's disease, Parkinson's disease, schizophrenia, andHuman Immunodeficiency Virus (HIV) dementia; obesity; metabolicdisorders such as insulin related deficiencies and lipid profiles,hepatic diseases, diabetes, and appetite disorders; cancer chemotherapy;benign prostatic hypertrophy; irritable bowel syndrome; biliarydiseases; ovarian disorders; marijuana abuse; and alcohol, opioid,nicotine, or cocaine addiction.

In another aspect, where the lipophilic active agent within thecompositions and methods of the invention is nicotine compound, thecondition is a nicotine-related disorder such as tobaccodependence/addiction, Parkinson's disease, ulcerative colitis,Alzheimer's disease, schizophrenia, Attention Deficit HyperactivityDisorder (ADHD), Tourette's syndrome, ulcerous colitis, andpost-smoking-cessation weight control.

In another aspect, where the lipophilic active agent within thecompositions and methods of the invention is an NSAID as describedherein, the condition is pain, fever, and/or an inflammatory-relateddisease or disorder, including but not limited to asthma, chronicobstructive pulmonary disease, pulmonary fibrosis, inflammatory boweldisease, irritable bowel syndrome, inflammatory pain, fever, migraine,headache, low back pain, fibromyalgia, myofascial disorders, viralinfections (e.g. influenza, common cold, herpes zoster, hepatitis C andAIDS), bacterial infections, fungal infections, dysmenorrhea, burns,surgical or dental procedures, malignancies (e.g. breast cancer, coloncancer, and prostate cancer), hyperprostaglandin E syndrome, classicBartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis,juvenile arthritis, rheumatoid arthritis, rheumatic fever, ankylosingspondylitis, Hodgkin's disease, systemic lupus erythematosus,vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis,scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis,stroke, diabetes mellitus, neurodegenerative disorders such asAlzheimer's disease and multiple sclerosis, autoimmune diseases,allergic disorders, rhinitis, ulcers, coronary heart disease,sarcoidosis and any other disease with an inflammatory component.

In another aspect, where the lipophilic active agent within thecompositions and methods of the invention is a vitamin, the condition isa vitamin deficiency or condition associated with the lipophilicvitamin. In a particular aspect, where the vitamin is vitamin E asdescribed herein, the condition is vitamin E deficiency and/or a vitaminE related disease or disorder such as ataxia associated with vitamin Edeficiency.

In another aspect, a method is provided of treating a central nervoussystem disease, disorder, or condition, comprising administering any ofthe compositions disclosed herein to a subject in need thereof

In other aspects within the methods of treating a central nervous systemdisease, disorder, or condition in a subject in need thereof, thecentral nervous system disease, disorder, or condition

(which encompasses psychiatric/behavioral diseases or disorders) mayinclude, but is not limited to, acquired epileptiform aphasia, acutedisseminated encephalomyelitis, adrenoleukodystrophy, agenesis of thecorpus callosum, agnosia, aicardi syndrome, Alexander disease, Alpers'disease, alternating hemiplegia, Alzheimer's disease, amyotrophiclateral sclerosis, anencephaly, Angelman syndrome, angiomatosis, anoxia,aphasia, apraxia, arachnoid cysts, arachnoiditis, Arnold-chiarimalformation, arteriovenous malformation, Asperger's syndrome, ataxiatelangiectasia, attention deficit hyperactivity disorder, autism,auditory processing disorder, autonomic dysfunction, back pain, Battendisease, Behcet's disease, Bell's palsy, benign essential blepharospasm,benign focal amyotrophy, benign intracranial hypertension, bilateralfrontoparietal polymicrogyria, binswanger's disease, blepharospasm,Bloch-sulzberger syndrome, brachial plexus injury, brain abscess, braindamage, brain injury, brain tumor, spinal tumor, Brown-sequard syndrome,canavan disease, carpal tunnel syndrome (cts), causalgia, central painsyndrome, central pontine myelinolysis, centronuclear myopathy, cephalicdisorder, cerebral aneurysm, cerebral arteriosclerosis, cerebralatrophy, cerebral gigantism, cerebral palsy, charcot-marie-toothdisease, chiari malformation, chorea, chronic inflammatory demyelinatingpolyneuropathy (“CIDP”), chronic pain, chronic regional pain syndrome,Coffin lowry syndrome, coma (including persistent vegetative state),congenital facial diplegia, corticobasal degeneration, cranialarteritis, craniosynostosis, Creutzfeldt-jakob disease, cumulativetrauma disorders, Cushing's syndrome, cytomegalic inclusion body disease(“CIBD”), cytomegalovirus infection, dandy-walker syndrome, Dawsondisease, de morsier's syndrome, Dejerine-klumpke palsy, Dejerine-sottasdisease, delayed sleep phase syndrome, dementia, dermatomyositis,developmental dyspraxia, diabetic neuropathy, diffuse sclerosis,dysautonomia, dyscalculia, dysgraphia, dyslexia, dystonia, earlyinfantile epileptic encephalopathy, empty sella syndrome, encephalitis,encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy,Erb's palsy, erythromelalgia, essential tremor, Fabry's disease, Fahr'ssyndrome, fainting, familial spastic paralysis, febrile seizures, fishersyndrome, Friedreich's ataxia, Gaucher's disease, Gerstmann's syndrome,giant cell arteritis, giant cell inclusion disease, globoid cellleukodystrophy, gray matter heterotopia, Guillain-barre syndrome, htiv-1associated myelopathy, Hallervorden-spatz disease, head injury,headache, hemifacial spasm, hereditary spastic paraplegia, heredopathiaatactica polyneuritiformis, herpes zoster oticus, herpes zoster,hirayama syndrome, holoprosencephaly, Huntington's disease,hydranencephaly, hydrocephalus, hypercortisolism, hypoxia,immune-mediated encephalomyelitis, inclusion body myositis,incontinentia pigmenti, infantile phytanic acid storage disease,infantile refsum disease, infantile spasms, inflammatory myopathy,intracranial cyst, intracranial hypertension, Joubert syndrome,Kearns-sayre syndrome, Kennedy disease, kinsbourne syndrome, Klippelfeil syndrome, Krabbe disease, Kugelberg-welander disease, kuru, laforadisease, Lambert-eaton myasthenic syndrome, Landau-kleffner syndrome,lateral medullary (Wallenberg) syndrome, learning disabilities, leigh'sdisease, Lennox-gastaut syndrome, Lesch-nyhan syndrome, leukodystrophy,lewy body dementia, lissencephaly, locked-in syndrome, Lou Gehrig'sdisease, lumbar disc disease, lyme disease—neurological sequelae,machado-joseph disease (spinocerebellar ataxia type 3), macrencephaly,megalencephaly, Melkersson-rosenthal syndrome, Meniere's disease,meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly,migraine, Miller Fisher syndrome, mini-strokes, mitochondrialmyopathies, mobius syndrome, monomelic amyotrophy, motor neuronedisease, motor skills disorder, moyamoya disease, mucopolysaccharidoses,multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis,multiple system atrophy with postural hypotension, muscular dystrophy,myalgic encephalomyelitis, myasthenia gravis, myelinoclastic diffusesclerosis, myoclonic encephalopathy of infants, myoclonus, myopathy,myotubular myopathy, myotonia congenita, narcolepsy, neurofibromatosis,neuroleptic malignant syndrome, neurological manifestations of aids,neurological sequelae of lupus, neuromyotonia, neuronal ceroidlipofuscinosis, neuronal migration disorders, niemann-pick disease, non24-hour sleep-wake syndrome, nonverbal learning disorder,O'sullivan-mcleod syndrome, occipital neuralgia, occult spinaldysraphism sequence, ohtahara syndrome, olivopontocerebellar atrophy,opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension,overuse syndrome, palinopsia, paresthesia, Parkinson's disease,paramyotonia congenita, paraneoplastic diseases, paroxysmal attacks,parry-romberg syndrome (also known as rombergs syndrome),pelizaeus-merzbacher disease, periodic paralyses, peripheral neuropathy,persistent vegetative state, pervasive developmental disorders, photicsneeze reflex, phytanic acid storage disease, pick's disease, pinchednerve, pituitary tumors, pmg, polio, polymicrogyria, polymyositis,porencephaly, post-polio syndrome, postherpetic neuralgia (“PHN”),postinfectious encephalomyelitis, postural hypotension, Prader-willisyndrome, primary lateral sclerosis, prion diseases, progressivehemifacial atrophy (also known as Romberg's syndrome), progressivemultifocal leukoencephalopathy, progressive sclerosing poliodystrophy,progressive supranuclear palsy, pseudotumor cerebri, ramsay-huntsyndrome (type I and type II), Rasmussen's encephalitis, reflexsympathetic dystrophy syndrome, refsum disease, repetitive motiondisorders, repetitive stress injury, restless legs syndrome,retrovirus-associated myelopathy, rett syndrome, Reye's syndrome,Romberg's syndrome, rabies, Saint Vitus' dance, Sandhoff disease,schizophrenia, Schilder's disease, schizencephaly, sensory integrationdysfunction, septo-optic dysplasia, shaken baby syndrome, shingles,Shy-drager syndrome, Sjogren's syndrome, sleep apnea, sleeping sickness,snatiation, Sotos syndrome, spasticity, spina bifida, spinal cordinjury, spinal cord tumors, spinal muscular atrophy, spinal stenosis,Steele-richardson-olszewski syndrome, see progressive supranuclearpalsy, spinocerebellar ataxia, stiff-person syndrome, stroke,Sturge-weber syndrome, subacute sclerosing panencephalitis, subcorticalarteriosclerotic encephalopathy, superficial siderosis, sydenham'schorea, syncope, synesthesia, syringomyelia, tardive dyskinesia,Tay-sachs disease, temporal arteritis, tetanus, tethered spinal cordsyndrome, Thomsen disease, thoracic outlet syndrome, tic douloureux,Todd's paralysis, Tourette syndrome, transient ischemic attack,transmissible spongiform encephalopathies, transverse myelitis,traumatic brain injury, tremor, trigeminal neuralgia, tropical spasticparaparesis, trypanosomiasis, tuberous sclerosis, vasculitis includingtemporal arteritis, Von Hippel-lindau disease (“VHL”), Viliuiskencephalomyelitis (“VE”), Wallenberg's syndrome, Werdnig-hoffmandisease, west syndrome, whiplash, Williams syndrome, Wilson's disease,and Zellweger syndrome. It is thus appreciated that all CNS-relatedstates and disorders could be treated through the BBB route of drugdelivery.

In some embodiments, a CNS disease, disorder, or condition according toembodiments of the present invention may be selected from a metabolicdisease, a behavioral disorder, a personality disorder, dementia, acancer, a neurodegenerative disorder, pain, a viral infection, a sleepdisorder, a seizure disorder, acid lipase disease, Fabry disease,Wernicke-Korsakoff syndrome, ADHD, anxiety disorder, borderlinepersonality disorder, bipolar disorder, depression, eating disorder,obsessive-compulsive disorder, schizophrenia, Alzheimer's disease, Barthsyndrome and Tourette's syndrome, Canavan disease, Hallervorden-Spatzdisease, Huntington's disease, Lewy Body disease, Lou Gehrig's disease,Machado-Joseph disease, Parkinson's disease, or Restless Leg syndrome.In some embodiments, the CNS disease, disorder, or condition is pain andis selected from neuropathic pain, central pain syndrome, somatic pain,visceral pain, and/or headache.

As used herein, the term “subject” treated by the presently disclosedmethods in their many aspects is desirably a human subject, although itis to be understood that the methods described herein are effective withrespect to all vertebrate species, which are intended to be included inthe term “subject.” Accordingly, a “subject” can include a human subjectfor medical purposes, such as for the diagnosis or treatment of anexisting disease, disorder, condition or the prophylactic diagnosis ortreatment for preventing the onset of a disease, disorder, or conditionor an animal subject for medical, veterinary purposes, or developmentalpurposes. Suitable animal subjects include mammals including, but notlimited to, primates, e.g., humans, monkeys, apes, gibbons, chimpanzees,orangutans, macaques and the like; bovines, e.g., cattle, oxen, and thelike; ovines, e.g., sheep and the like; caprines, e.g., goats and thelike; porcines, e.g., pigs, hogs, and the like; equines, e.g., horses,donkeys, zebras, and the like; felines, including wild and domesticcats; canines, including dogs; lagomorphs, including rabbits, hares, andthe like; and rodents, including mice, rats, guinea pigs, and the like.An animal may be a transgenic animal. In some aspects, the subject is ahuman including, but not limited to, fetal, neonatal, infant, juvenile,and adult subjects. Further, a “subject” can include a patient afflictedwith or suspected of being afflicted with a disease, disorder, orcondition. Thus, the terms “subject” and “patient” are usedinterchangeably herein. Subjects also include animal disease models(e.g., rats or mice used in experiments, and the like).

The term “effective amount,” as in “a therapeutically effective amount,”of a therapeutic agent refers to the amount of the agent necessary toelicit the desired biological response. As will be appreciated by thoseof ordinary skill in this art, the effective amount of an agent may varydepending on such factors as the desired biological endpoint, the agentto be delivered, the composition of the pharmaceutical composition, thetarget tissue or cell, and the like. More particularly, the term“effective amount” refers to an amount sufficient to produce the desiredeffect, e.g., to reduce or ameliorate the severity, duration,progression, or onset of a disease, disorder, or condition, or one ormore symptoms thereof; prevent the advancement of a disease, disorder,or condition, cause the regression of a disease, disorder, or condition;prevent the recurrence, development, onset or progression of a symptomassociated with a disease, disorder, or condition, or enhance or improvethe prophylactic or therapeutic effect(s) of another therapy.

Actual dosage levels of the active ingredients in the presentlydisclosed compositions can be varied so as to obtain an amount of theactive ingredient that is effective to achieve the desired therapeuticresponse for a particular subject, composition, route of administration,and disease, disorder, or condition without being toxic to the subject.The selected dosage level will depend on a variety of factors includingthe activity of the particular composition employed, the route ofadministration, the time of administration, the rate of excretion of theparticular composition being employed, the duration of the treatment,other drugs, and/or materials used in combination with the particularcomposition employed, the age, sex, weight, condition, general healthand prior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician having ordinary skill in the art can readily determine andprescribe the effective amount of the presently disclosed compositionrequired. Accordingly, the dosage range for administration may beadjusted by the physician as necessary, as described more fullyelsewhere herein.

EXAMPLES Example 1

A line of CBD and/or THC infused tea bags coming in a variety of flavorswas developed.

I. Ingredients:

Tea in leaf form, oil form, brewed form, organic and inorganic;

Evaporated dry non-fat milk;

CBD oil;

Hemp oil or compatible oil for ingestion;

Cannabis leaves, buds, oils; all strains with THC and/or CBD.

II. ViPova® Formulas:

IIA. CBD Tea

-   -   Combine evaporated nonfat, dry milk with any and all teas,        organic and inorganic;    -   Blend CBD oil with the tea leaves;    -   Dehydrate mixture of tea, CBD oil, and evaporated nonfat dry        milk in a food dehydrator;    -   End-product is ViPova® Tea with CBD enhancement only.

IIB. THC/CBD Tea

-   -   Combine evaporated nonfat, dry milk with any and all teas,        organic and inorganic;    -   Blend hemp or other ingestible oil with the tea leaves;    -   Add Cannabis leaves to above mixture;    -   Dehydrate mixture of tea, hemp or other ingestible oil, Cannabis        leaves, and evaporated nonfat dry milk;    -   End-product is ViPova® Tea with THC and CBD.

III. ViPova® Formulas: Specifications:

IIIA. CBD Tea

-   -   Tea: one tea bag contains 1 gram to 3 grams of tea leaves (dry        weight);    -   Evaporated dry non-fat milk: 0.10-1.00 grams;    -   CBD oil: 10 mgs.-25 mgs. per tea bag;

IIIB. THC/CBD Tea

-   -   Tea: one tea bag contains 1.5-12 grams tea leaves (dry weight)        per tea bag;    -   Evaporated dry milk: 0.10-6.00 grams per tea bag;    -   Hemp oil or other ingestible oil: 10 mgs.-25 mgs. per tea bag;    -   Cannabis leaves: 1.00-12.00 grams per tea bag;

IIIC. Production Equipment:

-   -   Commercial grinder for tea and/or Cannabis leaves;    -   Commercial mixer;    -   Commercial dehydrator;    -   Commercial tea bag filling machine.

IV. Flavorings

ViPova® Teas will provide a menu of flavorings for addition to tea bagsor loose tea selections including, but not limited to mint, citrus, andvanilla.

Example 2

A process for adhering CBD and/or THC to food products was developed.The food products may be selected from the group consisting of meats,fish, fruits, vegetables, dairy products, legumes, pastas, breads,grains, seeds, nuts, spices, and herbs. The process may or may notinvolve contacting the food product with sunflower and/or dry evaporatedmilk. The process involved the steps of:

-   -   1. A food product was saturated with 0-60 grams of CBD and/or        THC oil or extract.    -   2. The food product was placed on dehydrator paper and placed in        a food dehydrator for 0-24 hours.    -   3. The food product was removed from the dehydrator and stored        in air-tight containers.

Example 3

Black tea was formulated with various lipophilic active agents. Activeagents were dosed into the tea at a concentration of approximately 4.5mg of active ingredient per gram of finished product, using non-fat drymilk and sunflower seed oil as excipients. The following ingredientswere used for the formulation:

453 g of loose leaf black tea;

2265 mg active agent;

45 g of instant non-fat dry evaporated milk;

1132.5 mg of sunflower seed oil;

Ingredients were combined in a stainless steel bowl and mixed withgloved hands. A homogenous mixture was spread evenly on a dehydratortray and dehydrated for 30 minutes.

After cooling, the formulated tea was placed into a sterile zip-lockbag. The active ingredients that were formulated were: ASA (aspirin),ibuprofen, acetaminophen, diclofenac, indomethacin, piroxicam, nicotine,and vitamin E (α-tocopherol). The specific supplier information and lotnumbers for each active agent are shown below in Table 1.

TABLE 1 Active Agents Used for Formulations CAS Catalogue Lot CompoundNumber Supplier Number Number ASA (aspirin) 50-78-2 Sigma-Aldrich A2093#MKBQ8444V Ibuprofen 15687-27-1 Sigma-Aldrich I4883 #MKBQ4505VAcetaminophen 103-90-2 Sigma-Aldrich A5000 #MKBS7142V Diclofenac15307-79-6 Sigma-Aldrich D6899 #BCBN3367V Indomethacin 53-86-1Sigma-Aldrich I8280 #MKBR4530V Piroxicam 36322-90-4 Sigma-Aldrich P0847#SLBF3478V Nicotine 54-11-5 Sigma-Aldrich N3876 #1449194V Vitamin E10191-41-0 Sigma-Aldrich 258024 #MKBT5983V (α-tocopherol)

-   -   The Tea used was loose leaf English Breakfast Tea from Upton Tea        Imports (Holliston, Mass.).    -   The Sunflower Oil was Whole Foods brand organic sunflower oil.    -   The non-fat dry milk power was NowFoods brand organic non-fat        dry milk.    -   The dehydrator used was a Presto Dehydrator, model #06300.

Each component of the formulation was weighed out and combined asdescribed in the above procedure. The weights of the individual activeagents for each formulation are summarized below in Table 2.

TABLE 2 Formulation of Active Agents Non- Seed Oil Compound Compound DrySunflower Yield Weight Fat Milk Tea Black Concentration Compound ASA(aspirin) 2267.1 mg 45.09 g 1135 mg 453.2 g 479.3 g 4.52 mg/g Ibuprofen2265.5 mg 45.05 g 1138 mg 453.8 g 488.1 g 4.51 mg/g Acetaminophen 2264.7mg 45.01 g 1136 mg 453.2 g 477.9 g 4.51 mg/g Diclofenac 2265.3 mg 45.06g 1133 mg 453.1 g 441.3 g 4.52 mg/g Indomethacin 2266.3 mg 44.99 g 1138mg 453.1 g 491.5 g 4.52 mg/g Piroxicam 2265.9 mg 45.25 g 1134 mg 453.6 g488.3 g 4.51 mg/g Nicotine 2264.9 mg 45.02 g 1133 mg 453.1 g 488.1 g4.52 mg/g Vitamin E (α- 2271.1 mg 45.05 g 1135 mg 453.2 g 480.2 g 4.53mg/g tocopherol)

For each formulation, the constituents were mixed by hand until ahomogeneous mixture was achieved, then spread evenly on dehydrator traysfor drying. Each formulation was dried for 30 minutes in dehydrator.After cooling, mixture was placed into Zip-Lock bag. After taring theanalytical balance for the Zip-Lock bag, the weight of the finalformulation was recorded and the concentration of active ingredients inthe formulation calculated (Table 2).

Example 4

As used herein, compositions incorporating DEHYDRATECH™ are compositionsthat incorporate a dehydrated mixture comprising a therapeuticallyeffective amount of a lipophilic active agent and an edible oilcomprising long chain fatty acids, particularly wherein dehydratedmixture is obtainable by the steps of:

-   -   i) combining a therapeutically effective amount of the        lipophilic active agent with the edible oil comprising long        chain fatty acids; and    -   ii) dehydrating the product of step (i), thereby producing the        dehydrated mixture.

This study was designed to principally assess the relative ingestiblenicotine absorption performance of DEHYDRATECH™-powered formulationscompared to concentration-matched control formulations that lacked anyform of delivery enabling technology in rats. Nicotine was administeredin a nicotine polacrilex derivative format as is widely commercializedtoday in nicotine replacement therapy products such as chewing gums.Twelve male rats were divided into four groups of three, such thatDEHYDRATECH™ and control formulations were each tested at a 1 mg/Kg and10 mg/Kg dosage level. Formulations were administered orally and allrats were cannulated for blood collection at multiple intervals over an8 hour duration post-dosing with the first data collection at the15-minute mark. Urine and feces were also collected for up to a 24-hourduration post-dosing, and essential organ tissue samples were alsocollected for examination after the study. All samples were subjected toanalytical testing in order to quantify the levels of nicotine therein,as well as the levels of three major liver metabolites thereof,hydroxycotinine, nicotine N′-oxide and cotinine, in order to assess therelative metabolite levels absorbed by the different formulations.

Results & Observations

The DEHYDRATECH™ formulations generally achieved faster absorption,higher peak absorption and higher overall quantities of nicotine, onaverage, in the blood than the concentration-matched controlformulations at both the 1 mg and 10 mg/Kg doses tested. Furthermore, aspreviously reported, there were no obvious signs of gastrointestinaldistress such as vomiting or diarrhea indicating that the animalsappeared to tolerate the treatment well.

Nicotine blood levels were evaluated multiple times over a period of 8hours after dosing. In the 10 mg/Kg dosing arm, the control formulationrequired nearly 3 hours to reach similar levels of blood absorption thatthe DEHYDRATECH™ formulation reached in only 15 minutes. Furthermore,the DEHYDRATECH™ formulation went on thereafter to demonstrate peakplasma levels that were 148% of those achieved by the controlformulation. If replicated in human studies, these findings aresuggestive that DEHYDRATECH™'s technology could prove more effective inelevating blood nicotine levels through edible formats much more quicklyand substantially than previously theorized, potentially makingingestible nicotine preparations a viable alternative to today'savailable product formats while also leading to a more rapid nicotinecraving satiation.

Analysis of the liver metabolites revealed, as expected, that overalllevels in the blood of two of the three metabolites studied were higherin the control group than in the DEHYDRATECH™ formulation group at the10 mg/Kg dose. This result was especially pronounced in the 45-minute to2-hour time interval post-dosing which is consistent with the expectedtiming of release of metabolites in higher quantity into the bloodstreamby the liver following normal physiological processing of ingestednicotine with the control preparation, compared to the DehydraTECH™technology that is believed to elude first pass liver metabolism. TheDEHYDRATECH™ formulation also demonstrated lower quantities of nicotinein the rat urine at both doses, which is consistent with the fact thatthe levels of nicotine in the rat blood remained higher over theduration of the study with the DEHYDRATECH™ formulation than with thecontrol. The study also revealed that the DEHYDRATECH™ formulation atthe 10 mg/Kg level achieved up to 5.6-times as much nicotine uponanalysis of the rat brain tissue than was recovered with the matchingcontrol formulation. These findings together perhaps suggestprolongation of nicotine effectiveness with the DEHYDRATECH™ formulationwhich may also be beneficial in humans to control cravings over anextended time-period from a single edible nicotine dose.

Example 5

In this study, the exposure and distribution of nicotine and its majormetabolites were evaluated following oral administration of two separateformulations (Reference and Test Nicotine Polacrilex) in maleSprague-Dawley rats.

Formulations were administered orally (PO) at 10 mg/kg. Followingdosing, blood samples were collected up to 1 hour post dose; and urineand fecal samples were collected up to 24 hours post dose. Brain, liver,and kidney tissue were collected at 1 hour (Groups 1 & 5), 4 hours(Groups 2 & 6), following the 8 hour urine and feces sample collection(Groups 3 & 7), or following the 24 hour urine and feces samplecollection (Groups 4 & 8). Blood, urine, feces, and tissueconcentrations of each analyte were determined by LC-MS/MS. Plasmapharmacokinetic parameters were determined using WinNonlin (v8.0).Brain, liver, and kidney pharmacokinetic parameters were determinedusing WinNonlin (v8.0) software with sparse sampling.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group1), maximum plasma concentrations (average of 144±68.2 ng/mL) ofnicotine were observed between 30 minutes and 1 hour post dosing. Theaverage half-life after oral dosing could not be determined. The averageexposure for nicotine (Group 1) based on the dose normalized AUClast was8.71±2.76 hr*kg*ng/mL/mg.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group1), maximum plasma concentrations (average of 9.79±3.56 ng/mL) ofhydroxycotinine metabolite were observed between 45 minutes and 1 hourpost dosing. The average half-life after oral dosing could not bedetermined. The average exposure for hydroxycotinine (Group 1) based onthe dose normalized AUClast was 0.420±0.146 hr*kg*ng/mL/mg.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group1), maximum plasma concentrations (average of 179±54.9 ng/mL) ofnicotine-n-oxide metabolite were observed between 30 minutes and 1 hourpost dosing. The average half-life after oral dosing could not bedetermined. The average exposure for nicotine-n-oxide (Group 1) based onthe dose normalized AUClast was 11.2±3.32 hr*kg*ng/mL/mg.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group1), maximum plasma concentrations (average of 193±58.6 ng/mL) ofcotinine metabolite were observed at 1 hour post dosing. The averagehalf-life after oral dosing could not be determined. The averageexposure for cotinine (Group 1) based on the dose normalized AUClast was10.9±2.90 hr*kg*ng/mL/mg.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group2), maximum plasma concentrations (average of 350±256 ng/mL) of nicotinewere observed between 8 minutes and 1 hour post dosing. The averagehalf-life after oral dosing could not be determined. The averageexposure for nicotine (Group 2) based on the dose normalized AUClast was21.3±13.7 hr*kg*ng/mL/mg.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group2), maximum plasma concentrations (average of 20.1±13.3 ng/mL) ofhydroxycotinine metabolite were observed at 1 hour post dosing. Theaverage half-life after oral dosing could not be determined. The averageexposure for hydroxycotinine (Group 2) based on the dose normalizedAUClast was 1.15±0.928 hr*kg*ng/mL/mg.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group2), maximum plasma concentrations (average of 409±235 ng/mL) ofnicotine-n-oxide metabolite were observed between 12 minutes and 1 hourpost dosing. The average half-life after oral dosing could not bedetermined. The average exposure for nicotine-n-oxide (Group 2) based onthe dose normalized AUClast was 26.8±18.3 hr*kg*ng/mL/mg.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group2), maximum plasma concentrations (average of 359±236 ng/mL) of cotininemetabolite were observed between 45 minutes and 1 hour post dosing. Theaverage half-life after oral dosing could not be determined. The averageexposure for cotinine (Group 2) based on the dose normalized AUClast was22.5±16.7 hr*kg*ng/mL/mg.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group3), maximum plasma concentrations (average of 176±71.2 ng/mL) ofnicotine were observed between 30 minutes and 1 hour post dosing. Theaverage half-life after oral dosing could not be determined. The averageexposure for nicotine (Group 3) based on the dose normalized AUClast was11.7±4.62 hr*kg*ng/mL/mg. On average, 1.04±0.49% and 0.03±0.04% of thedose (unchanged dose) was found in urine and feces, respectively, afterPO dosing.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group3), maximum plasma concentrations (average of 13.4±5.95 ng/mL) ofhydroxycotinine metabolite were observed between 45 minutes 1 hour postdosing. The average half-life after oral dosing could not be determined.The average exposure for hydroxycotinine (Group 3) based on the dosenormalized AUClast was 0.672±0.386 hr*kg*ng/mL/mg. On average,1.10±0.64% and 0.03% (n=1) of the dose was found in urine and feces,respectively, after PO dosing.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group3), maximum plasma concentrations (average of 283±134 ng/mL) ofnicotine-n-oxide metabolite were observed between 30 minutes and 1 hourpost dosing. The average half-life after oral dosing could not bedetermined. The average exposure for nicotine-n-oxide (Group 3) based onthe dose normalized AUClast was 17.8±7.29 hr*kg*ng/mL/mg. On average,9.36±4.36% and 0.07% (n=1) of the dose was found in urine and feces,respectively, after PO dosing.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group3), maximum plasma concentrations (average of 304±103 ng/mL) of cotininemetabolite were observed at 1 hour post dosing. The average half-lifeafter oral dosing could not be determined. The average exposure forcotinine (Group 3) based on the dose normalized AUClast was 15.4±4.99hr*kg*ng/mL/mg. On average, 0.99±0.48% and 0.03±0.02% of the dose wasfound in urine and feces, respectively, after PO dosing.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group4), maximum plasma concentrations (average of 210±68.6 ng/mL) ofnicotine were observed between 15 minutes and 1 hour post dosing. Theaverage half-life after oral dosing was 0.949±0.214 hours. The averageexposure for nicotine (Group 4) based on the dose normalized AUClast was13.0±4.98 hr*kg*ng/mL/mg. On average, 3.31±0.91% and 0.09±0.07% of thedose (unchanged dose) was found in urine and feces, respectively, afterPO dosing.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group4), maximum plasma concentrations (average of 14.3±4.74 ng/mL) ofhydroxycotinine metabolite were observed between 45 minutes and 1 hourpost dosing. The average half-life after oral dosing could not bedetermined. The average exposure for hydroxycotinine (Group 4) based onthe dose normalized AUClast was 0.751±0.389 hr*kg*ng/mL/mg. On average,6.48±2.12% and 0.03±0.02% of the dose was found in urine and feces,respectively, after PO dosing.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group4), maximum plasma concentrations (average of 223±71.9 ng/mL) ofnicotine-n-oxide metabolite were observed between 15 minutes and 1 hourpost dosing. The average half-life after oral dosing was 1.38 hours. Theaverage exposure for nicotine-n-oxide (Group 4) based on the dosenormalized AUClast was 15.0±6.27 hr*kg*ng/mL/mg. On average, 20.3±6.90%of the dose was found in urine after PO dosing. All concentrations infeces were below the limit of quantitation.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Group4), maximum plasma concentrations (average of 247±49.4 ng/mL) ofcotinine metabolite were observed between 45 minutes and 1 hour postdosing. The average half-life after oral dosing could not be determined.The average exposure for cotinine (Group 4) based on the dose normalizedAUClast was 14.0±2.60 hr*kg*ng/mL/mg. On average, 5.30±2.18% and0.16±0.08% of the dose was found in urine and feces, respectively, afterPO dosing.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Groups1-4), the average (±SE) C_(max) for nicotine in brain tissue was427±66.5 ng/g, the t_(max) was 4 hours, the half-life could not bedetermined, and the exposure for nicotine based on the dose normalizedAUClast was 588±53.8 hr*kg*ng/g/mg. After PO dosing of ReferenceNicotine Polacrilex, the average (±SE) C_(max) for hydroxycotininemetabolite in brain tissue was 51.8±9.14 ng/g, the t_(max) was 8 hours,the half-life could not be determined, and the exposure forhydroxycotinine metabolite based on the dose normalized AUClast was95.5±12.1 hr*kg*ng/g/mg. After PO dosing of Reference NicotinePolacrilex, the majority of the concentrations were below the limit ofquantitation and therefore, the pharmacokinetic parameters were not ableto be calculated. After PO dosing of Reference Nicotine Polacrilex, theaverage (±SE) C_(max) for cotinine metabolite in brain tissue was722±135 ng/g, the t_(max) was 8 hours, the half-life could not bedetermined, and the exposure for cotinine metabolite based on the dosenormalized AUClast was 1332±208 hr*kg*ng/g/mg.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Groups1-4), the average (±SE) C_(max) for nicotine in liver tissue was1300±308 ng/g, the t_(max) was 4 hours, the half-life could not bedetermined, and the exposure for nicotine based on the dose normalizedAUClast was 1737±167 hr*kg*ng/g/mg. After PO dosing of ReferenceNicotine Polacrilex, the average (±SE) C_(max) for hydroxycotininemetabolite in liver tissue was 102±13.5 ng/g, the t_(max) was 8 hours,the half-life could not be determined, and the exposure forhydroxycotinine metabolite based on the dose normalized AUClast was205±26.3 hr*kg*ng/g/mg. After PO dosing of Reference NicotinePolacrilex, the average (±SE) C_(max) for nicotine-n-oxide metabolite inliver tissue was 4.51±1.58 ng/g, the t_(max) was 8 hours, the half-lifecould not be determined, and the exposure for nicotine-n-oxidemetabolite based on the dose normalized AUClast was 6.86±1.83hr*kg*ng/g/mg. After PO dosing of Reference Nicotine Polacrilex, theaverage (±SE) C_(max) for cotinine metabolite in liver tissue was905±119 ng/g, the t_(max) was 8 hours, the half-life could not bedetermined, and the exposure for cotinine metabolite based on the dosenormalized AUClast was 1620±189 hr*kg*ng/g/mg.

Following PO dosing of Reference Nicotine Polacrilex at 10 mg/kg (Groups1-4), the average (±SE) C_(max) for nicotine in kidney tissue was8965±1519 ng/g, the t_(max) was 4 hours, the half-life could not bedetermined, and the exposure for nicotine based on the dose normalizedAUClast was 12267±1173 hr*kg*ng/g/mg. After PO dosing of ReferenceNicotine Polacrilex, the average (±SE) C_(max) for hydroxycotininemetabolite in kidney tissue was 200±44.1 ng/g, the t_(max) was 24 hours,the half-life could not be determined, and the exposure forhydroxycotinine metabolite based on the dose normalized AUClast was391±47.7 hr*kg*ng/g/mg. After PO dosing of Reference NicotinePolacrilex, the average (±SE) C_(max) for nicotine-n-oxide metabolite inkidney tissue was 20.5±4.26 ng/g, the t_(max) was 4 hours, the half-lifecould not be determined, and the exposure for nicotine-n-oxidemetabolite based on the dose normalized AUClast was 23.4±2.80hr*kg*ng/g/mg. After PO dosing of Reference Nicotine Polacrilex, theaverage (±SE) C_(max) for cotinine metabolite in kidney tissue was1775±217 ng/g, the t_(max) was 8 hours, the half-life could not bedetermined, and the exposure for cotinine metabolite based on the dosenormalized AUClast was 3436±374 hr*kg*ng/g/mg.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 5),maximum plasma concentrations (average of 416±255 ng/mL) of nicotinewere observed between 12 minutes and 1 hour post dosing. The averagehalf-life after oral dosing could not be determined. The averageexposure for nicotine (Group 5) based on the dose normalized AUClast was28.7±13.8 hr*kg*ng/mL/mg.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 5),maximum plasma concentrations (average of 13.9±3.07 ng/mL) ofhydroxycotinine metabolite were observed at 1 hour post dosing. Theaverage half-life after oral dosing could not be determined. The averageexposure for hydroxycotinine (Group 5) based on the dose normalizedAUClast was 0.671±0.167 hr*kg*ng/mL/mg.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 5),maximum plasma concentrations (average of 267±56.1 ng/mL) ofnicotine-n-oxide metabolite were observed between 45 minutes and 1 hourpost dosing. The average half-life after oral dosing could not bedetermined. The average exposure for nicotine-n-oxide (Group 5) based onthe dose normalized AUClast was 19.3±3.45 hr*kg*ng/mL/mg.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 5),maximum plasma concentrations (average of 381±81.8 ng/mL) of cotininemetabolite were observed at 1 hour post dosing. The average half-lifeafter oral dosing could not be determined. The average exposure forcotinine (Group 5) based on the dose normalized AUClast was 21.3±5.76hr*kg*ng/mL/mg.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 6),maximum plasma concentrations (average of 315±142 ng/mL) of nicotinewere observed between 15 minutes and 1 hour post dosing. The averagehalf-life after oral dosing could not be determined. The averageexposure for nicotine (Group 6) based on the dose normalized AUClast was21.5±10.8 hr*kg*ng/mL/mg.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 6),maximum plasma concentrations (average of 11.6±2.62 ng/mL) ofhydroxycotinine metabolite were observed between 45 minutes and 1 hourpost dosing. The average half-life after oral dosing could not bedetermined. The average exposure for hydroxycotinine (Group 6) based onthe dose normalized AUClast was 0.581±0.149 hr*kg*ng/mL/mg.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 6),maximum plasma concentrations (average of 246±120 ng/mL) ofnicotine-n-oxide metabolite were observed between 15 minutes and 1 hourpost dosing. The average half-life after oral dosing could not bedetermined. The average exposure for nicotine-n-oxide (Group 6) based onthe dose normalized AUClast was 15.6±8.37 hr*kg*ng/mL/mg.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 6),maximum plasma concentrations (average of 315±76.8 ng/mL) of cotininemetabolite were observed between 45 minutes and 1 hour post dosing. Theaverage half-life after oral dosing could not be determined. The averageexposure for cotinine (Group 6) based on the dose normalized AUClast was17.7±5.25 hr*kg*ng/mL/mg.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 7),maximum plasma concentrations (average of 253±40.0 ng/mL) of nicotinewere observed between 12 minutes and 1 hour post dosing. The averagehalf-life after oral dosing could not be determined. The averageexposure for nicotine (Group 7) based on the dose normalized AUClast was18.3±6.21 hr*kg*ng/mL/mg. On average, 2.02±1.21% and 0.04±0.04% of thedose (unchanged dose) was found in urine and feces, respectively, afterPO dosing.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 7),maximum plasma concentrations (average of 12.7±4.62 ng/mL) ofhydroxycotinine metabolite were observed at 1 hour post dosing. Theaverage half-life after oral dosing could not be determined. The averageexposure for hydroxycotinine (Group 7) based on the dose normalizedAUClast was 0.620±0.253 hr*kg*ng/mL/mg. On average, 0.97±0.34% and 0.02%(n=1) of the dose was found in urine and feces, respectively, after POdosing.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 7),maximum plasma concentrations (average of 276±67.5 ng/mL) ofnicotine-n-oxide metabolite were observed between 15 minutes and 1 hourpost dosing. The average half-life after oral dosing was 2.84 hours. Theaverage exposure for nicotine-n-oxide (Group 7) based on the dosenormalized AUClast was 17.6±6.17 hr*kg*ng/mL/mg. On average, 9.91±4.61%and 0.12% of the dose was found in urine and feces, respectively, afterPO dosing.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 7),maximum plasma concentrations (average of 317±100 ng/mL) of cotininemetabolite were observed at 1 hour post dosing. The average half-lifeafter oral dosing could not be determined. The average exposure forcotinine (Group 7) based on the dose normalized AUClast was 16.6±4.69hr*kg*ng/mL/mg. On average, 1.39±0.80% and 0.02±0.01% of the dose wasfound in urine and feces, respectively, after PO dosing.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 8),maximum plasma concentrations (average of 593±641 ng/mL) of nicotinewere observed between 8 minutes and 1 hour post dosing. The averagehalf-life after oral dosing could not be determined; however, thehalf-life for one rat was 0.737 hours. The average exposure for nicotine(Group 8) based on the dose normalized AUClast was 38.0±38.5hr*kg*ng/mL/mg. On average, 5.91±3.24% and 0.06±0.03% of the dose(unchanged dose) was found in urine and feces, respectively, after POdosing.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 8),maximum plasma concentrations (average of 17.4±13.8 ng/mL) ofhydroxycotinine metabolite were observed between 45 minutes and 1 hourpost dosing. The average half-life after oral dosing could not bedetermined. The average exposure for hydroxycotinine (Group 8) based onthe dose normalized AUClast was 0.940±0.788 hr*kg*ng/mL/mg. On average,9.07±3.61% and 0.02±0.01% of the dose was found in urine and feces,respectively, after PO dosing.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 8),maximum plasma concentrations (average of 357±306 ng/mL) ofnicotine-n-oxide metabolite were observed between 15 minutes and 1 hourpost dosing. The average half-life after oral dosing could not bedetermined; however, the half-life for one rat was 0.888 hours. Theaverage exposure for nicotine-n-oxide (Group 8) based on the dosenormalized AUClast was 27.5±23.8 hr*kg*ng/mL/mg. On average, 39.5±9.71%and 0.08% of the dose was found in urine and feces, respectively, afterPO dosing.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Group 8),maximum plasma concentrations (average of 441±333 ng/mL) of cotininemetabolite were observed at 1 hour post dosing. The average half-lifeafter oral dosing could not be determined. The average exposure forcotinine (Group 8) based on the dose normalized AUClast was 25.8±20.0hr*kg*ng/mL/mg. On average, 8.23±2.58% and 0.18±0.10% of the dose wasfound in urine and feces, respectively, after PO dosing.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Groups5-8), the average (±SE) C_(max) for nicotine in brain tissue was1260±200 ng/g, the t_(max) was 1 hour, the half-life was 21.6 hours, andthe exposure for nicotine based on the dose normalized AUClast was1300±125 hr*kg*ng/g/mg. After PO dosing of Test Nicotine Polacrilex, theaverage (±SE) C_(max) for hydroxycotinine metabolite in brain tissue was91.2±7.69 ng/g, the t_(max) was 24 hours, the half-life could not bedetermined, and the exposure for hydroxycotinine metabolite based on thedose normalized AUClast was 142±6.64 hr*kg*ng/g/mg. After PO dosing ofTest Nicotine Polacrilex, the average (±SE) C_(max) for nicotine-n-oxidemetabolite in brain tissue was 4.17±1.41 ng/g, the t_(max) was 1 hour,the half-life could not be determined, and the exposure fornicotine-n-oxide metabolite based on the dose normalized AUClast was2.70±1.05 hr*kg*ng/g/mg. After PO dosing of Test Nicotine Polacrilex,the average (±SE) C_(max) for cotinine metabolite in brain tissue was1322±219 ng/g, the t_(max) was 24 hours, the half-life could not bedetermined, and the exposure for cotinine metabolite based on the dosenormalized AUClast was 2172±189 hr*kg*ng/g/mg.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Groups5-8), the average (±SE) C_(max) for nicotine in liver tissue was2702±308 ng/g, the t_(max) was 1 hour, the half-life was 18.9 hours, andthe exposure for nicotine based on the dose normalized AUClast was2989±277 hr*kg*ng/g/mg. After PO dosing of Test Nicotine Polacrilex, theaverage (±SE) C_(max) for hydroxycotinine metabolite in liver tissue was232±41.2 ng/g, the t_(max) was 24 hours, the half-life could not bedetermined, and the exposure for hydroxycotinine metabolite based on thedose normalized AUClast was 338±37.6 hr*kg*ng/g/mg. After PO dosing ofTest Nicotine Polacrilex, the average (±SE) C_(max) for nicotine-n-oxidemetabolite in liver tissue was 6.69±1.67 ng/g, the t_(max) was 1 hour,the half-life could not be determined, and the exposure fornicotine-n-oxide metabolite based on the dose normalized AUClast was8.74±2.56 hr*kg*ng/g/mg. After PO dosing of Test Nicotine Polacrilex,the average (±SE) C_(max) for cotinine metabolite in liver tissue was1451±157 ng/g, the t_(max) was 24 hours, the half-life could not bedetermined, and the exposure for cotinine metabolite based on the dosenormalized AUClast was 2505±139 hr*kg*ng/g/mg.

Following PO dosing of Test Nicotine Polacrilex at 10 mg/kg (Groups5-8), the average (±SE) C_(max) for nicotine in kidney tissue was8930±676 ng/g, the t_(max) was 1 hour, the half-life was 24.2 hours, andthe exposure for nicotine based on the dose normalized AUClast was12717±1354 hr*kg*ng/g/mg. After PO dosing of Test Nicotine Polacrilex,the average (±SE) C_(max) for hydroxycotinine metabolite in kidneytissue was 244±16.5 ng/g, the t_(max) was 24 hours, the half-life couldnot be determined, and the exposure for hydroxycotinine metabolite basedon the dose normalized AUClast was 449±24.1 hr*kg*ng/g/mg. After POdosing of Test Nicotine Polacrilex, the average (±SE) C_(max) fornicotine-n-oxide metabolite in kidney tissue was 28.0±6.34 ng/g, thet_(max) was 1 hour, the half-life could not be determined, and theexposure for nicotine-n-oxide metabolite based on the dose normalizedAUClast was 38.0±5.57 hr*kg*ng/g/mg. After PO dosing of Test NicotinePolacrilex, the average (±SE) C_(max) for cotinine metabolite in kidneytissue was 2466±321 ng/g, the t_(max) was 24 hours, the half-life couldnot be determined, and the exposure for cotinine metabolite based on thedose normalized AUClast was 4300±280 hr*kg*ng/g/mg.

All publications, patent applications, patents, and other referencesmentioned in the specification are indicative of the level of thoseskilled in the art to which the presently disclosed subject matterpertains. All publications, patent applications, patents, and otherreferences are herein incorporated by reference to the same extent as ifeach individual publication, patent application, patent, and otherreference was specifically and individually indicated to be incorporatedby reference. It will be understood that, although a number of patentapplications, patents, and other references are referred to herein, suchreference does not constitute an admission that any of these documentsforms part of the common general knowledge in the art.

Although the foregoing subject matter has been described in some detailby way of illustration and example for purposes of clarity ofunderstanding, it will be understood by those skilled in the art thatcertain changes and modifications can be practiced within the scope ofthe appended claims.

1.-15. (canceled)
 16. Nicotine infused tobacco leaves, comprising: (a) atherapeutically effective amount of nicotine; (b) an edible oil; and (c)tobacco leaves.
 17. The nicotine infused tobacco leaves according toclaim 16, wherein the edible oil comprises one or more glyceroltriesters, the triesters comprising medium chain (C₇-C₁₃) or long chain(C₁₄-C₂₂) fatty acids.
 18. The nicotine infused tobacco leaves accordingto claim 16, wherein the edible oil is a vegetable, nut, or seed oil.19. The nicotine infused tobacco leaves according to claim 18, whereinthe edible oil is coconut oil, peanut oil, soybean oil, safflower seedoil, corn oil, olive oil, castor oil, cottonseed oil, arachis oil,sunflower seed oil, coconut oil, palm oil, or rapeseed oil.
 20. Thenicotine infused tobacco leaves according to claim 16, wherein theedible oil is sunflower oil.
 21. The nicotine infused tobacco leavesaccording to claim 16, further comprising one or more cannabinoids. 22.The nicotine infused tobacco leaves according to claim 21, furthercomprising THC or CBD.
 23. The nicotine infused tobacco leaves accordingto claim 16, further comprising a flavoring agent.
 24. The nicotineinfused tobacco leaves according to claim 23, wherein the flavoringagent is selected from the group consisting of vanilla, vanillin, ethylvanillin, orange oil, peppermint oil, strawberry, raspberry, andmixtures thereof.
 25. The nicotine infused tobacco leaves according toclaim 16, wherein the tobacco leaves have been dehydrated.
 26. Thenicotine infused tobacco leaves according to claim 16, wherein thenicotine infused tobacco leaves further comprise terpenes andterpenoids, NSAIDs, vitamins, phosphodiesterase type 5 (PDE5)inhibitors, Maca extract, estrogen, progestin, testosterone,buprenorphine, and scopolamine.
 27. A process for making nicotineinfused tobacco leaves: (a) contacting tobacco leaves with an edible oilcomprising nicotine; and (b) dehydrating the tobacco leaves; therebyproducing nicotine infused tobacco.
 28. The process according to claim27, wherein the nicotine tobacco leaves are dehydrated bylyophilization.
 29. The process according to claim 27, wherein theedible oil is a vegetable, nut, or seed oil.
 30. The process accordingto claim 29, wherein the edible oil is coconut oil, peanut oil, soybeanoil, safflower seed oil, corn oil, olive oil, castor oil, cottonseedoil, arachis oil, sunflower seed oil, coconut oil, palm oil, or rapeseedoil.
 31. The process according to claim 30, wherein the edible oil issunflower oil.
 32. The process according to claim 27, further comprisingone or more cannabinoids.
 33. The process according to claim 32, whereinthe one or more cannabinoids are THC or CBD.
 34. The process accordingto claim 27, wherein the nicotine infused tobacco leaves furthercomprise terpenes and terpenoids, NSAIDs, vitamins, phosphodiesterasetype 5 (PDE5) inhibitors, Maca extract, estrogen, progestin,testosterone, buprenorphine, and scopolamine.
 35. The process accordingto claim 27, wherein the nicotine infused tobacco leaves furthercomprise a flavoring agent selected from the group consisting ofvanilla, vanillin, ethyl vanillin, orange oil, peppermint oil,strawberry, raspberry, and mixtures thereof.